WO2012098281A2

WO2012098281A2 - Trp-receptor-modulating peptides and uses thereof

Info

Publication number: WO2012098281A2
Application number: PCT/ES2012/070026
Authority: WO
Inventors: Antonio Ferrer Montiel; Asia Fernández Carvajal; Gregorio FERNÁNDEZ BALLESTER; José Manuel GONZÁLEZ ROS; Carlos BELMONTE MARTÍNEZ; Pierluigi VALENTE; María CAMBPRUBI ROBLES; Félix VIANA DE LA IGLESIA; Ana GOMIS GARCÍA; Wim Van Den Nest; Cristina CARREÑO SERRAÏMA
Original assignee: Universidad Miguel Hernández De Elche; Bcn Peptides, S.A.; Consejo Superior De Investigaciones Científicas
Priority date: 2011-01-19
Filing date: 2012-01-19
Publication date: 2012-07-26
Also published as: WO2012098281A3

Abstract

The invention relates to peptides that can modulate the activity of TRP receptors and to the use thereof for treating and/or preventing pain, inflammation, pruritus, respiratory tract illnesses and/or disorders, and/or illnesses and/or disorders associated with calcium imbalances.

Description

MODULATING PEPTIDES OF TRP RECEPTORS AND THEIR USES

FIELD OF THE INVENTION

The invention relates to peptides that have the ability to modulate the activity of TRP receptors and their uses. More specifically, the authors of the invention have identified peptide inhibitors that are capable of specifically binding to TRPV1, TRPM8 and / or TRPA1 thermoreceptors and inhibiting the activity of said receptors.

BACKGROUND OF THE INVENTION

Nociceptive neurons recognize mechanical, thermal and chemical stimuli that can be harmful to the body. Therefore, they are considered guardians of tissue integrity and nociception an essential safety mechanism for life. At the molecular level, they have in their terminals a set of protein receptors prepared to recognize and transduce harmful physical (mechanical, osmotic and thermal) and chemical stimuli. In this sense, the human being has receptors capable of recognizing the spectrum of temperatures from very cold (<17 ° C) to very hot (> 50 ° C) [Belmonte et al. (2008) Mol. Pain 4: 14].

The channels or receivers TRP (Transient Potential Receptors) are receptors that constitute a large family subdivided into 8 subfamilies: TRPC, TRPM, TRPV, TRPA, TRPP, TRPML, TRPN (present in invertebrates) and TRPY (in yeasts). These receptors play a fundamental role in the transduction of the different somatosensory modalities, including thermosensing, pheromone reception, vascular tone regulation, nociception and pain. It is increasingly clear that TRP receptors are very important in sensory physiology and that their functional alteration, either by mutations or by harmful stimuli or pro-inflammatory factors, leads to pathological states in humans.

TRP receptors are expressed in a wide variety of multicellular organisms comprising yeasts, worms, fruit flies, zebrafish, and mammals. All TRP receptors are cationic channels that allow the flow of Ca ²⁺ and Na ⁺ , although according to the isoform the permeability and selectivity with respect to mono or divalent cations varies substantially. Its pattern of tissue distribution is very wide, appearing expressed in virtually all tissues, especially in the central and peripheral nervous systems, in which they play a crucial role in sensory transduction, converting environmental stimuli into changes in neuronal membrane excitability [Venkatachalam K. et al. (2007) Annu. Rev. Biochem. 76: 387-417]. In addition, its permeability to the Ca ²⁺ cation leads to the activation of cellular transduction signals that also contribute to sensory transmission. Genetic association studies have linked mutations in these receptors with human diseases. Thus, for example, mutations in the TRPP family produce the autosomal dominant disease known as renal polycystitis, the TRPML mutation leads to type IV mucolipidosis, the alteration of TRPC6 produces segmental glomerulosclerosis, an autosomal dominant condition, and the TRPM6 mutation causes hypomagnesemia and hypocalcaemia [Venkatachalam K. et al. cited ad supra].

The TRPV subfamily (Transient Potential Receptors activated by

Vanilloides) in mammals is made up of 6 members divided into 2 groups according to the degree of homology, TRPV1 -4 and TRPV5-6. The receptors that recognize thermal stimuli, or thermoreceptors or thermo-TRPs, are TRPV1 -4, and among them the TRPV1 receptor stands out as a molecular threshold sensor for harmful temperatures for the organism [Caterina MJ et al. (2001) Annu. Rev. Neurosci. 24: 487-517]. The TRPV1 receptor has become a crucial target in the transduction of painful signals, especially in the etiology of inflammatory pain. Its extensive tissue and cellular distribution, together with the enhancement of its ionic channel activity by pro-inflammatory mediators released during tissue damage, have placed this receptor as a critical mediator of inflammatory sensitization of nociceptors resulting in the manifestation of hypersensitivity in the damaged area. A cluster of research results indicates that TRPV1 participates in the onset and maintenance of neurogenic inflammation that usually accompanies tissue damage. In this sense, the genetic or pharmacological elimination of the receptor in animals produces a reduction of the inflammatory process that translates into an attenuation of thermal hyperalgesia [Venkatachalam K. et al. cited ad supra]. It has also been described that the gene expression of TRPV1 increases significantly in fimatous and erythematotelangiectatic rosacea and that the ionic channels of TRP can be a target for the treatment of rosacea [Sulk M. et al., J. Invest. Dermatol 201 1 Dec 22. doi: 10.1038 / jid. 201 1.424]. The thermoreceptors involved in cold sensitivity are TRPA1, which is activated at temperatures below 17 ° C, and TRPM8, which is activated at temperatures below 30 ° C. In addition to its role in nociception at cold temperatures, its alteration in inflammatory and neuropathic processes has been linked to cold hyperalgesia. Therefore, compounds that inhibit the activity of these receptors may have anti-hyperalgesic activity [da Costa DS et al. (2010) Pain 148: 431-437; Viana F. et al. (2009) Expert. Opin. Ther. Pal 19: 1787-1799; Knowlton WM et al. (2010) Pain 150: 340-350; Katsura H. et al. (2006) Exp. Neurol. 200: 1 12-123].

The involvement of TRP receptors in respiratory diseases and disorders has also been described: TRPV1 is overexpressed in asthma as well as in other diseases or inflammatory disorders of the respiratory tract, while the early inflammatory response to cigarette smoke is mediated. completely due to the activity of neuronal TRPA1 [Nassini R. et al. (2010) Curr. Opin. Investig. Drugs 1 1: 535-542]. Likewise, it has been described that the activation of TRPM8 induces the release of histamine by mast cells, which contributes to the development of allergic responses of the respiratory tract, such as asthma [Cho Y. et al. (2010) Cell Calcium 48: 202-208]. TRPV1, TRPA1 and / or TRPM8 antagonists therefore have potential application as antitussives, antiallergics and / or anti-inflammatories for the treatment and / or prevention of respiratory tract diseases.

In addition to its role in nociception and cold hyperalgesia, the TRPM8 receptor seems to be involved in the development of cancer, because its levels are markedly elevated in the cancer cells of prostate and pancreas cancer. Inhibitors of this receptor have shown anti-proliferative activity in cell cultures of prostate tumor cells [Knowlton W.M. et al. (2010) Curr. Pharm Biotechnol Nov 8; Yee N.S. et al. (2010) Cancer Lett. 297: 49-55; Bai V.U. et al. (2010) Int. J. Oncol. 36: 443-450].

The TRPV1, TRPA1 and TRPM8 receptors are calcium channels. Due to the important role that calcium regulation plays in many cellular processes, including cell activation, gene expression, cell traffic and cell death due to apoptosis, dishomeostasis or calcium imbalance is implicated in many diseases and disorders related to such activities. cell phones, such as dermatological diseases and disorders, Neurological, neurodegenerative, urological, intestinal, respiratory, digestive, metabolic, hepatic, renal, cancer and sensitivity to pain and touch. The flow of calcium through the plasma membrane of skin cells is a critical signaling element involved in cell differentiation in the skin epidermis [Dotto GP (1999) Crit. Rev. Oral Biol. Med. 10: 442-457]. By regulating or modulating the calcium pathway, which is a critical point for the growth of skin cells, skin diseases or disorders that are characterized by epidermal hyperplasia, a condition in which can be treated or prevented which skin cells proliferate too quickly and differ little. These diseases include psoriasis, and basal and squamous cell carcinomas. Many of the dermatological diseases and disorders are accompanied by itching (pruritus). Itching and pain share many similarities in their mechanism of action; both are related to the activation of C fibers, enhanced by the increase in temperature and mediators and / or receptors of inflammation such as TRPV1, and both can be repressed with opioid analgesics. The decrease in neuronal excitability, in particular the excitability of the C fibers by administration of TRPV1, TRPA1 and / or TRPM8 antagonists can alleviate the pruritus associated not only with diseases and disorders of the skin and / or mucous membranes but also the pruritus associated with other diseases or epithelial, gastrointestinal, cardiovascular system, urinary tract, endocrine, cerebral, reproductive system, respiratory tract and / or cancer disorders.

The treatment of pain is one of the challenges facing current medicine and for which there are no highly effective compounds. The pain can be divided into "nociceptive" and "neuropathic." Nociceptive pain includes pain induced by tissue damage, such as a cut or a burn, and inflammatory pain, such as arthritis. It is due to the activation of pain-sensitive nerve fibers, both somatic and visceral. Nociceptive pain has been traditionally treated by the administration of non-opioid analgesics, including acetylsalicylic acid, choline, magnesium trisalicylate, acetaminophen / paracetamol, ibuprofen, fenoprofen, diflunisal and naproxen, among others. Neuropathic pain refers to pain induced by damage to the peripheral or central nervous system and is characterized by an aberrant somatosensory process [McQuay HJ (1997) Acta Anaesthesiol. Scand. 41: 175-183]. In contrast to the immediate pain caused by tissue damage, neuropathic pain may develop days or months after traumatic damage. Neuropathic pain is associated with chronic sensory discomforts that include pain. spontaneous, hyperalgesia {ie feeling more pain than the stimulus justifies) and allodynia (ie a condition in which non-painful conventional stimuli induce pain). In humans, prevalent symptoms include cold hyperalgesia and mechanical allodynia. Examples of neuropathic pain syndromes include those due to the progression of a disease, such as diabetic neuropathy, multiple sclerosis or post-herpetic neuralgia; those initiated by harm, such as amputation; or prolonged damage in an accident (for example, avulsion); and those caused by nerve damage, such as chronic alcoholism, viral infection, hypothyroidism, uremia or vitamin deficiencies. Neuropathic pain is often resistant to therapies with known medications. Such therapies include opioids, antiepileptics, NMDA glutamate receptor antagonists and tricyclic antidepressants. However, none of these treatments is particularly effective. Also, pain can be classified as acute and chronic, depending on the duration of the pain.

TRP receptors are involved in both neuropathic and nociceptive pain. There is evidence that TRPV1, TRPM8 and / or TRPA1 antagonists are capable of attenuating hyperalgesia, allodynia or mechanical hypersensitivity in models of inflammatory or neuropathic pain [DiMarzo V. et al. (2002) Curr. Opin. Neurobiol 12: 372-379; Eid S.R. et al. (2008) Mol. Pain 4:48; Gauchan P. et al. (2009) Neurosci. Lett. 458: 93-95].

TRPV1 and TRPA1 are overexpressed in painful gastrointestinal diseases, such as inflammatory bowel disease, Crohn's disease or colitis [Geppetti P. et al. (2004) Br. J. Pharmacol. 141: 1313-1320; Kimball ES et al. (2007) Neurogastroenterol. Motil 19: 390-400]. Likewise, TRPV1, TRPM8 and TRPA1 have been identified in the urinary tract of humans and have been described as being involved in bladder distension [Lashinger ES et al. (2008) Am. J. Physiol. Renal Physiol. 295: F803-810], so that antagonists of said TRP receptors may have potential application in the treatment of diseases or disorders related to the urinary system as well as associated pain, such as incontinence, overactive bladder, cystitis or the syndrome of painful bladder In addition, TRPA1 is activated by stimulation of muscarinic acetylcholine type 1 receptors (M1 AChR) [Jordt SE et al. (2004) Nature 427: 260-265], and it is well known that antimuscarinic compounds are useful in the treatment of diseases or disorders of the urinary system such as overactive bladder, so that blocking TRPA1 could alleviate such conditions without the effects side effects that are associated with muscarinic antagonists. TRPV1 also seems to be involved in epithelial diseases or disorders, such as allergic contact dermatitis and also seems to have a cardioprotective role [Nilius B. et al. (2007) Physiol. Rev. 87: 165-217]. TRPA1 also plays a key role in the development of skin disorders [Atoyan R. et al. (2009) J. Invest. Dermatol 129: 2312-2315].

The validation of TRPV1, TRPM8 and TRPA1 as therapeutic targets and their involvement in a multitude of diseases and / or disorders that occur with pain, inflammation and / or pruritus or in diseases and / or disorders of the respiratory tract or related to calcium imbalances , have led to the development by the cosmetic and pharmaceutical industry of different activators and inhibitors of said receptors. Thus, among the agonists of TRPV1 is capsaicin, which is used in topical applications for the treatment of different conditions (ALGRX 4975 from AlgoRx / Anesiva for localized injections or transaicin, originally NGX-4010 from Merck / Neurogen, in dermal patches ), resiniferatoxin, a toxin isolated from Euphorbia resinífera, olvanil (originally NE-19550 from P&G), as well as the compounds SDZ-249482 and SDZ-249665 from Novartis, which have shown good efficacy in animal models of pain and inflammation [ Messeguer A. et al. (2006) Curr. Neuropharmacol 4: 1-9]. TRPA1 agonists include cinnamaldehyde, allyl isothiocinanate, diallyl disulfide, iciline, cinnamon oil, gaulteria oil, acrolein and mustard oil. TRPM8 receptor activators include menthol, icicline, eucalyptol, linalool, geraniol and hydroxycitronellal.

Despite the therapeutic potential shown by these agonists, their oral bioavailability is very limited, and is partly restricted due to the burning or irritation sensation that accompanies their topical administration.

An alternative to TRP receptor agonists has been the development of antagonists that induce receptor inhibition without the described side effects associated with its activation. The cosmetic and pharmaceutical sector have developed different antagonists of TRPV1, TRPM8 and / or TRPA1, such as for example and without limitation the compounds SB-705498 of GlaxoSmith-Kline, NGD-8243 of Merck / Neurogen, AMG-517 of Amgen, GRC -621 to Glenmark, capsacepin, 5-iodine-resiniferatoxin, methoctramine, or those described in WO 00/56761 A1, WO 02/30956 A1, WO 03/097670 A1, US 2009/0143377 A1, US 2009/0176883 A1 , US 2009/0264480 A1, WO 2010/004390 A1, US 2010/0137259 A1,

WO 2010/141805 A1, WO 2010/125469 A1, WO 2010/144680 A1, WO 2010/103381 A1, or US 2008/0287398 A1 among others. These antagonists are in different stages of development and currently none of those who have entered clinical studies have successfully completed them.

Therefore, although several modulators of TRP receptor activity have been described, there is a need to find alternatives to inhibitors known in the state of the art.

SUMMARY OF THE INVENTION

In one aspect, the invention relates to a peptide, hereinafter peptide of the invention, selected from the group consisting of:

(i) peptide comprising the sequence SEQ ID NO: 1 or a functionally equivalent variant, where the length of said peptide is equal to or less than 25 amino acids and where the asparagine of the sequence SEQ ID NO: 1 remains unchanged;

(ii) peptide comprising the sequence SEQ ID NO: 2 or a functionally equivalent variant, wherein the length of said peptide is equal to or less than 25 amino acids;

(iii) peptide comprising the sequence SEQ ID NO: 3 or a functionally equivalent variant, where the length of said peptide is equal to or less than 25 amino acids, the arginine and glutamine of SEQ ID NO: 3 remain unchanged and where the peptide is not the sequence peptide SEQ ID NO: 4;

(iv) peptide comprising the sequence SEQ ID NO: 5 or a functionally equivalent variant, where the length of said peptide is equal to or less than 20 amino acids, and where the peptide is not the sequence peptide

SEQ ID NO: 6;

(v) peptide comprising the sequence SEQ ID NO: 7 or a functionally equivalent variant, where the length of said peptide is equal to or less than 20 amino acids, and where the asparagine of SEQ ID NO: 7 closest to the C-terminal remains unchanged;

(vi) peptide comprising the sequence SEQ ID NO: 8 or a functionally equivalent variant, wherein the length of said peptide is equal or less than 20 amino acids, and where the valine and / or tryptophan of SEQ ID NO: 8 remain unchanged;

(vii) peptide comprising the sequence SEQ ID NO: 9 or a functionally equivalent variant, where the length of said peptide is equal to or less than 20 amino acids, and where the isoleucine of SEQ ID NO: 9 remains unchanged;

(viii) peptide comprising the sequence SEQ ID NO: 10 or a functionally equivalent variant, where the length of said peptide is equal to or less than 20 amino acids, and where the amino acid of the V-terminal / end of SEQ ID NO: 10 it can only be isoleucine or leucine, and the valine of said sequence remains unchanged;

(ix) peptide comprising the sequence SEQ ID NO: 1 1 or a functionally equivalent variant, where the length of said peptide is equal to or less than 20 amino acids, and where the histidine of SEQ ID NO: 1 1 remains unchanged;

(x) peptide comprising the sequence SEQ ID NO: 12 or a functionally equivalent variant, where the length of said peptide is equal to or less than 20 amino acids, and where the peptide is not the sequence peptide SEQ ID NO: 13;

their stereoisomers, mixtures thereof and / or their cosmetically or pharmaceutically acceptable salts.

In another aspect, the invention relates to a process for preparing the peptide of the invention, its stereoisomers, mixtures thereof and / or its cosmetically or pharmaceutically acceptable salts, characterized in that it is carried out in solid phase or in solution or is a combination. of solid phase and solution synthesis.

In another aspect, the invention relates to a cosmetic or pharmaceutical composition comprising at least one peptide of the invention or a functionally equivalent variant, its stereoisomers, mixtures thereof and / or its cosmetically or pharmaceutically acceptable salts, together with at least a cosmetic or pharmaceutically acceptable adjuvant.

In another aspect, the invention relates to the use of at least one peptide selected from the group consisting of: (i) peptide comprising the sequence SEQ ID NO: 1 or a functionally equivalent variant, where the length of said peptide is equal to or less than 25 amino acids and where the asparagine of the sequence SEQ ID NO: 1 remains unchanged;

(iii) peptide comprising the sequence SEQ ID NO: 3 or a functionally equivalent variant, where the length of said peptide is equal to or less than 25 amino acids and where the arginine and glutamine of the

SEQ ID NO: 3 remain unchanged;

(iv) peptide comprising the sequence SEQ ID NO: 5 or a functionally equivalent variant, wherein the length of said peptide is equal to or less than 20 amino acids;

(vi) peptide comprising the sequence SEQ ID NO: 8 or a functionally equivalent variant, where the length of said peptide is equal to or less than 20 amino acids, and where the valine and / or tryptophan of SEQ ID NO: 8 is they remain unchanged;

(ix) peptide comprising the sequence SEQ ID NO: 1 1 or a functionally equivalent variant, wherein the length of said peptide is equal or less than 20 amino acids, and where the histidine of SEQ ID NO: 1 1 remains unchanged;

(x) peptide comprising the sequence SEQ ID NO: 12 or a functionally equivalent variant, wherein the length of said peptide is equal to or less than 20 amino acids;

its stereoisomers, mixtures thereof and / or their cosmetically or pharmaceutically acceptable salts, in the manufacture of a cosmetic or pharmaceutical composition for the treatment and / or prevention of pain, inflammation, pruritus, diseases and / or respiratory tract disorders and / or diseases and / or disorders associated with calcium imbalances.

In another aspect, the invention relates to the use of at least one peptide selected from the group consisting of:

(i) peptide comprising the sequence SEQ ID NO: 1 or a functionally equivalent variant, where the length of said peptide is equal to or less than 25 amino acids and where the asparagine of the sequence

SEQ ID NO: 1 remains unchanged;

(iii) peptide comprising the sequence SEQ ID NO: 3 or a functionally equivalent variant, where the length of said peptide is equal to or less than 25 amino acids and where the arginine and glutamine of SEQ ID NO: 3 remain unchanged;

its stereoisomers, mixtures thereof and / or their cosmetically or pharmaceutically acceptable salts, in the manufacture of a cosmetic or pharmaceutical composition for the treatment and / or care of the skin, mucous membranes and / or nails.

(iii) peptide comprising the sequence SEQ ID NO: 3 or a functionally equivalent variant, wherein the length of said peptide is equal or less than 25 amino acids and where the arginine and glutamine of SEQ ID NO: 3 remain unchanged;

its stereoisomers, mixtures thereof and / or their cosmetically or pharmaceutically acceptable salts, in the manufacture of a cosmetic or pharmaceutical composition for the inhibition of the TRPV1 receptor.

(i) peptide comprising the sequence SEQ ID NO: 5 or a functionally equivalent variant, wherein the length of said peptide is equal to or less than 20 amino acids;

(ii) peptide comprising the sequence SEQ ID NO: 7 or a functionally equivalent variant, where the length of said peptide is equal to or less than 20 amino acids, and where the asparagine of SEQ ID NO: 7 closest to the C-terminal remains unchanged;

(iii) peptide comprising the sequence SEQ ID NO: 8 or a functionally equivalent variant, where the length of said peptide is equal to or less than 20 amino acids, and where the valine and / or tryptophan of SEQ ID NO: 8 is they remain unchanged;

its stereoisomers, mixtures thereof and / or their cosmetically or pharmaceutically acceptable salts, in the manufacture of a cosmetic or pharmaceutical composition for inhibition of the TRPM8 receptor.

(i) peptide comprising the sequence SEQ ID NO: 9 or a functionally equivalent variant, where the length of said peptide is equal to or less than 20 amino acids, and where the isoleucine of SEQ ID NO: 9 remains unchanged;

(ii) peptide comprising the sequence SEQ ID NO: 10 or a functionally equivalent variant, where the length of said peptide is equal to or less than 20 amino acids, and where the amino acid of the V-terminal / end of SEQ ID NO: 10 it can only be isoleucine or leucine, and the valine of said sequence remains unchanged; (iii) peptide comprising the sequence SEQ ID NO: 1 1 or a functionally equivalent variant, where the length of said peptide is equal to or less than 20 amino acids, and where the histidine of SEQ ID NO: 1 1 remains unchanged;

(iv) peptide comprising the sequence SEQ ID NO: 12 or a functionally equivalent variant, wherein the length of said peptide is equal to or less than 20 amino acids;

its stereoisomers, mixtures thereof and / or their cosmetically or pharmaceutically acceptable salts, in the manufacture of a cosmetic or pharmaceutical composition for inhibition of the TRPA1 receptor.

(i) peptide comprising the sequence SEQ ID NO: 5 or a functionally equivalent variant, where the length of said peptide is equal to or less than 20 amino acids, and where the peptide is not the sequence peptide

SEQ ID NO: 6;

its stereoisomers, mixtures thereof and / or pharmaceutically acceptable salts thereof, in the manufacture of a medicament for the treatment of cancer.

BRIEF DESCRIPTION OF THE FIGURES

Figure 1 shows that the Palmitoil-SEQ ID NO: 16-NH ₂ peptide inhibited the release of capsaicin-induced α-CGRP in rat sensory neurons. The release of α-CGRP was induced by applying 1 μΜ of capsaicin for 5 minutes. Neural cultures were incubated with the Palmitoil-SEQ ID NO: 16-NH ₂ peptide a a concentration of 10 μΜ for 60 minutes before the application of capsaicin. The amount of α-CGRP released was determined by an immunochemiluminescence assay. Values are shown as mean ± standard deviation from the average (mean ± sem), with n (number of neurons) ≥25.

Figure 2 shows the inhibition by the Palmitoil-SEQ ID NO: 16-NH ₂ peptide of capsaicin-induced nerve activity in rat knee nociceptor fibers, (ad) Instantaneous frequency of nerve impulse produced by intra-arterial administration of 100 μί of capsaicin 10 μΜ (a) before administration of 100 μί of the Palmitoil-SEQ ID NO: 16-NH ₂ peptide at 100 μΜ, (b) 15 min after administration of 100 μΙ_ of the Palmitoil-SEQ ID NO: 16-NH ₂ at 100 μΜ, (c) 30 min after the administration of 100 μΙ_ of the Palmitoil-SEQ ID peptide NO: 16-NH ₂ at 100 μΜ and (d) 45 min after the administration of 100 μΙ_ of the peptide Palmitoil-SEQ ID NO: 16-NH ₂ at 100 μΜ.

Figure 3 shows the inhibition by the Palmitoil-SEQ ID NO: 16-NH ₂ peptide of thermal hyperalgesia and scratching behavior in response to the itching caused by bile duct ligation.

DETAILED DESCRIPTION OF THE INVENTION

The authors of the present invention have found that the function of the TRPV1, TRPM8 and TRPA1 receptors can be modulated by peptides designed from the sequences of the TRPV1, TRPM8 and TRPA1 proteins, respectively. Thus, the inventors have determined that peptides whose sequence derives from the TRPV1 sequence are capable of blocking the TRPV1 receptor channel, peptides whose sequence derives from the TRPM8 sequence are capable of blocking the TRPM8 receptor channel and peptides whose sequence derives from the TRPA1 sequence are capable of blocking the TRPA1 receptor channel.

Definitions

In order to facilitate the understanding of the present invention, the meanings of some terms and expressions as used in the context of the invention are included.

The term "treatment", as used in the context of this specification, means the administration of a peptide according to the invention to alleviate or eliminate a disease or disorder or reduce or eliminate one or more symptoms associated with said disease or disorder The term "treatment" also encompasses alleviating or eliminating the physiological sequelae of the disease or disorder.

The term "prevention", as used in the present invention, refers to the ability of a peptide of the invention to prevent, delay or hinder the onset or development of a disease or disorder before its appearance.

In the context of the present invention, "skin" means the set of layers that comprise it from the most superficial layer or stratum corneum to the deepest layer or hypodermis, both included. These layers are composed of different types of cells such as keratinocytes, fibroblasts, melanocytes and / or adipocytes among others.

In the context of the present invention, the term "skin" includes the scalp.

In the context of the present invention "skin, mucous and / or nail care" comprises the prevention of diseases and / or disorders of the skin, mucous membranes and / or nails.

The term "non-cyclic aliphatic group" is used in the present invention to encompass linear or branched alkyl, alkenyl and alkynyl groups.

The term "alkyl group" refers to a saturated, linear or branched group, having between 1 and 24, preferably between 1 and 16, more preferably between 1 and 14, even more preferably between 1 and 12, still more preferably 1, 2, 3, 4, 5 or 6 carbon atoms and that is attached to the rest of the molecule through a single bond, including, for example and without limitation, methyl, ethyl, isopropyl, isobutyl, irec-butyl, heptyl, octyl , decyl, dodecyl, lauryl, hexadecyl, octadecyl, amyl, 2-ethylhexyl, 2-methylbutyl, 5-methylhexyl and the like.

The term "alkenyl group" refers to a group, linear or branched, having between 2 and 24, preferably between 2 and 16, more preferably between 2 and 14, even more preferably between 2 and 12, still more preferably 2, 3 , 4, 5 or 6 carbon atoms, with one or more carbon-carbon double bonds, preferably with 1, 2 or 3 carbon-carbon double bonds, conjugated or unconjugated, which is attached to the rest of the molecule by a single bond including, for example and not limited to, the similar vinyl group (-CH 2 = CH _2), allyl (-CH2-CH = CH _2), oleyl, linoleyl and.

The term "alkynyl group" refers to a group, linear or branched, having between 2 and 24, preferably between 2 and 16, more preferably between 2 and 14, even more preferably between 2 and 12, still more preferably 2, 3, 4, 5 or 6 carbon atoms with one or more carbon-carbon triple bonds, preferably 1, 2 or 3 carbon-carbon triple bonds, conjugated or unconjugated, which is bound to the rest of the molecule by a single bond, including, for example and without limitation, the ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, pentinyl group, such as 1 -pentinyl, and the like. The alkynyl groups may also contain one or more carbon-carbon double bonds, including, for example and without limitation, the but-1-en-3-inyl, pent-4-en-1-ynyl group and the like.

The term "alicyclyl group" is used in the present invention to encompass, for example and without limitation, cycloalkyl or cycloalkenyl or cycloalkynyl groups.

The term "cycloalkyl" refers to a saturated mono- or polycyclic aliphatic group having between 3 and 24, preferably between 3 and 16, more preferably between 3 and 14, even more preferably between 3 and 12, still more preferably 3, 4 , 5 or 6 carbon atoms and which is attached to the rest of the molecule by a single bond, including, for example and without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, methyl cyclohexyl, dimethyl cyclohexyl, octahydroindene, decahydronaphthalene, dodecahydrofenalene and the like.

The term "cycloalkenyl" refers to a non-aromatic mono- or polycyclic aliphatic group having between 5 and 24, preferably between 5 and 16, more preferably between 5 and 14, even more preferably between 5 and 12, still more preferably 5 or 6 carbon atoms, with one or more carbon-carbon double bonds, preferably 1, 2 6 3 carbon-carbon double bonds, conjugated or unconjugated, and which is attached to the rest of the molecule by a single bond, including, for example and without limiting sense, the cyclopent-1-in-1-yl group and the like.

The term "cycloalkynyl" refers to a non-aromatic mono- or polycyclic aliphatic group having between 8 and 24, preferably between 8 and 16, more preferably between 8 and 14, even more preferably between 8 and 12, still more preferably 8 or 9 carbon atoms, with one or more carbon-carbon triple bonds, preferably 1, 2 6 3 carbon-carbon triple bonds, conjugated or unconjugated, and which is attached to the rest of the molecule by a single bond, including, for example and without limitation, the cyclooct-2-in-1-yl group and the like. The cycloalkynyl groups may also contain one or more carbon-carbon double bonds, including, for example and without limitation, the cyclooct-4-en-2-inyl group and the like. The term "aryl group" refers to an aromatic group having between 6 and 30, preferably between 6 and 18, more preferably between 6 and 10, even more preferably 6 or 10 carbon atoms, comprising 1, 2, 3 or 4 aromatic rings, linked by a carbon-carbon bond or condensate, including, for example and without limitation, phenyl, naphthyl, diphenyl, indenyl, phenanthryl or anthranyl among others; or to an aralkyl group.

The term "aralkyl group" refers to an alkyl group substituted with an aromatic group, having between 7 and 24 carbon atoms and including, for example and without limitation, - (CH ₂ ) i-6-phenyl, - (CH ₂ ) i-6- (1-naphthyl), - (CH ₂ ) i-6- (2-naphthyl), - (CH ₂ ) i-6-CH (phenyl) ₂ and the like.

The term "heterocyclyl group" refers to a 3-10 membered hydrocarbon ring, in which one or more of the ring atoms, preferably 1, 2 or 3 of the ring atoms, is a non-carbon element, such as for example nitrogen, oxygen or sulfur and which can be saturated or unsaturated. For the purposes of this invention, the heterocycle may be a monocyclic, bicyclic or tricyclic cyclic system, which may include condensed ring systems; and the nitrogen, carbon or sulfur atoms may optionally be oxidized in the heterocyclyl radical; the nitrogen atom may be optionally quaternized; and the heterocyclyl radical may be partially or completely saturated or aromatic. More preferably, the term "heterocyclic" refers to a 5 or 6 membered ring. Examples of saturated heterocyclyl groups are dioxane, piperidine, piperazine, pyrrolidine, morpholine and thiomorpholine. Examples of aromatic heterocyclyl groups, also known as heteroaromatic groups are pyridine, pyrrole, furan, thiophene, benzofuran, imidazoline, quinolein, quinoline, pyridine. The term "heteroarylalkyl group" refers to an alkyl group substituted with a substituted or unsubstituted aromatic heterocyclyl group, the alkyl group having 1 to 6 carbon atoms and the aromatic heterocyclyl group having 2 to 24 carbon atoms and 1 to 3 atoms other than carbon and including, for example and without limitation, - (CH ₂ ) _1-6 -imidazolyl, - (CH ₂ ) _1-6 -triazolyl, - (CH ₂ ) _1-6 -thienyl, - ( CH ₂ ) _1-6 -furyl, - (CH ₂ ) _1-6 -pyrrolidinyl and the like.

As understood in this technical area, there may be a certain degree of substitution on the groups defined above. Thus, substitution may exist in the groups of the present invention where explicitly so indicated. References in this document to substituted groups in the groups herein The invention indicates that the specified radical may be substituted in one or more positions available with one or more substituents, preferably in 1, 2 or 3 positions, more preferably in 1 or 2 positions, still more preferably in 1 position. Such substituents include, for example and without limitation, CrC ₄ alkyl; hydroxyl; CrC ₄ alkoxy; Not me; CrC ₄ aminoalkyl; CrC ₄ carbonyloxy; CrC ₄ oxycarbonyl; halogen such as fluorine, chlorine, bromine and iodine; cyano; nitro; azido; CC ₄ alkylsulfonyl; thiol; CC ₄ alkylthio; aryloxy such as phenoxy;

where R _b and R _c are independently selected from the group consisting of H, alkyl AD _4, alkenyl C ₂ -C ₄ alkynyl , C ₂ -C _4, C3-C10, aryl _C6 Ci _8, C7-C17 aralkyl, 3-10-membered heterocyclyl or amino group protecting group.

Peptides modulating the activity of the TRP receptor channels

Therefore, in a first aspect, the invention relates to a peptide, hereinafter peptide of the invention, selected from the group consisting of:

(I) peptide comprising the sequence SEQ ID NO: 2 or a functionally equivalent variant, wherein the length of said peptide is equal to or less than 25 amino acids;

(V) peptide comprising the sequence SEQ ID NO: 5 or a functionally equivalent variant, where the length of said peptide is equal to or less than 20 amino acids, and where the peptide is not the sequence peptide SEQ ID NO: 6;

(v) peptide comprising the sequence SEQ ID NO: 7 or a functionally equivalent variant, where the length of said peptide is equal to or less than 20 amino acids, and where the asparagine of SEQ ID NO: 7 closest to the C-terminal remains unchanged; (vi) peptide comprising the sequence SEQ ID NO: 8 or a functionally equivalent variant, where the length of said peptide is equal to or less than 20 amino acids, and where the valine and / or tryptophan of SEQ ID NO: 8 is they remain unchanged;

(x) peptide comprising the sequence SEQ ID NO: 12 or a functionally equivalent variant, where the length of said peptide is equal to or less than 20 amino acids, and where the peptide is not the sequence peptide

SEQ ID NO: 13;

In a particular embodiment, the amino-terminal (/ V-terminal) and carboxy-terminal (C-terminal) ends of the peptide sequences may be chemically modified.

According to a preferred embodiment, the / V-terminal substituent is selected from the group consisting of H, a polymer derived from polyethylene glycol and R-CO-, where R is selected from the group consisting of C1-C24 alkyl radical substituted or not substituted, substituted or unsubstituted C ₂ -C ₂ 4 alkenyl, substituted or unsubstituted C ₂ -C 24 alkynyl, substituted or unsubstituted C 3 -C 24 cycloalkyl, substituted or unsubstituted C ₅ -C ₂₄ cycloalkenyl, substituted C ₈ -C ₂ 4 cycloalkenyl or unsubstituted, C ₆ -C ₃ aryl or substituted or unsubstituted, C7-C24 aralkyl substituted or not substituted, 3-10 heterocyclyl substituted or unsubstituted ring, and substituted or unsubstituted heteroarylalkyl of 2 to 24 carbon atoms and 1 to 3 atoms other than carbon and an alkyl chain of 1 to 6 carbon atoms and R -CO- is not an α-amino acid. More preferably, the end / V-terminal substituent is selected from the group consisting of H, a polymer derived from polyethylene glycol of molecular weight between 200 and 35,000 Daltons, acetyl, irec-butanoyl, prenyl, hexanoyl, 2-methylhexanoyl, cyclohexanecarboxyl, octanoyl, decanoyl, lauroyl, myristoyl, palmitoyl, stearoyl, oleoyl and linoleoyl. Even more preferably, the / V-terminal substituent is H, acetyl, lauroyl, myristoyl or palmitoyl. In an even more preferred embodiment, Ri is acetyl or palmitoyl.

According to another preferred embodiment, the C-terminal substituent is selected from the group consisting of -NR ^, -ORi, -SRi, where Ri and R ₂ are independently selected from the group consisting of H, a polymer derived from polyethylene glycol, C1-C24 substituted or unsubstituted alkyl, alkenyl C ₂ -C _{4 February} substituted or unsubstituted alkynyl , C ₂ -C _{4 February} substituted or unsubstituted cycloalkyl , C ₃ -C ₂₄ substituted or unsubstituted, cycloalkenyl C ₅ -C ₂₄ substituted or unsubstituted, C ₈ -C ₂₄ substituted or unsubstituted cycloalkynyl, C ₆ -C ₃ or substituted or unsubstituted aryl, C ₇ -C ₂₄ substituted or unsubstituted aralkyl, 3-10 substituted or unsubstituted 3-10 ring heterocyclyl substituted, and substituted or unsubstituted heteroarylalkyl of 2 to 24 carbon atoms and 1 to 3 atoms other than carbon where the alkyl chain is 1 to 6 carbon atoms and -NR- | R ₂ is not an α-amino acid. Optionally, R1 and _R2 may be joined by a carbon-carbon, saturated or unsaturated, forming a cycle with the nitrogen atom bond. More preferably the substituent of the C-terminal end is -NR- | R ₂ or -OR1. More preferably, R 1 and R ₂ are selected from the group consisting of H, a polymer derived from polyethylene glycol of molecular weight between 200 and 35,000 Daltons, methyl, ethyl, hexyl, dodecyl and hexadecyl. Even more preferably R1 is H and R ₂ is selected from the group consisting of H, methyl, ethyl, hexyl, dodecyl and hexadecyl. According to an even more preferred embodiment, the C-terminal substituent is selected from -OH and -NH ₂ .

The peptide of SEQ ID NO: 4 (ILWRVQRRRSACGFTLRNW) is described in

WO 01/57274 A2. The peptide of SEQ ID NO: 6 (YGWTIGQNCRQWG) is described in WO 01/31019 A2. The peptide of SEQ ID NO: 13 (DVIKALRLAMQL) is described in US 2008/0226664 A1. The peptides of the invention comprise a sequence that is derived from a region of the TRP receptors and, preferably, are selected from the group of sequences schematized in Table 1, in which their sequence identifier is detailed:

SEQUENCE IDENTIFIER

MGETVN SEQ ID NO: 1

NKIAQES SEQ ID NO: 2

IWKLQR SEQ ID NO: 3

FGYTVG SEQ ID NO: 5

TVQENN SEQ ID NO: 7

NDQVWK SEQ ID NO: 8

VGDIAE SEQ ID NO: 9

IAEVQK SEQ ID NO: 10

VQKHAS SEQ ID NO: 1 1

RIAMQV SEQ ID NO: 12

Table 1

In a particular embodiment, the peptide of the invention is selected from the group of sequences described in Table 2, which comprise the sequences SEQ ID NO: 1-3, SEQ ID NO: 5 and SEQ ID NO: 7-12 described above. They are shown together with the sequence identifier and its function (TRP receptor they inhibit).

SEQUENCE IDENTIFIER FUNCTION

MGETVN SEQ ID NO: 1 TRPV1 inhibitor

NKIAQES SEQ ID NO: 2 TRPV1 inhibitor

IWKLQR SEQ ID NO: 3 TRPV1 inhibitor

ALMGETVNKIAQ SEQ ID NO: 14 TRPV1 inhibitor

AQESKNIWKLQR SEQ ID NO: 15 TRPV1 inhibitor

MGETVN KIAQES SEQ ID NO: 16 TRPV1 inhibitor

MGETVNKIAQESKNIWKLQRA SEQ ID NO: 17 TRPV1 inhibitor MGETVNKIAQESKNIWKLQ SEQ ID NO: 18 TRPV1 inhibitor

MGETVNKIAQESKNIWK SEQ ID NO: 19 TRPV1 inhibitor

MGETVNKIAQESKNI SEQ ID NO 20 TRPV1 inhibitor

MGETVNKIAQE SEQ ID NO: 21 TRPV1 inhibitor

MGETVNKIAQ SEQ ID NO: 22 TRPV1 inhibitor

MGETVNKIA SEQ ID NO: 23 TRPV1 inhibitor

MGETVNKI SEQ ID NO 24 TRPV1 inhibitor

MGETVNK SEQ ID NO 25 TRPV1 inhibitor

VNKIAQES SEQ ID NO 26 TRPV1 inhibitor

TVNKIAQES SEQ ID NO 27 TRPV1 inhibitor

ETVNKIAQES SEQ ID NO 28 TRPV1 inhibitor

GETVNKIAQES SEQ ID NO 29 TRPV1 inhibitor

IWKLQRA SEQ ID NO: 30 TRPV1 inhibitor

FGYTVG SEQ ID NO:: 5 TRPM8 inhibitor

TVQENN SEQ ID NO:: 7 TRPM8 inhibitor

NDQVWK SEQ ID NO:: 8 TRPM8 inhibitor

FGYTVGTVQENN SEQ ID NO: 31 TRPM8 inhibitor

FGYTVGTVQENNDQVWKFQR SEQ ID NO: 32 TRPM8 inhibitor

VGDIAE SEQ ID NO:: 9 TRPA1 inhibitor

IAEVQK SEQ ID NO: 10 TRPA1 inhibitor

VQKHAS SEQ ID NO: 1 1 TRPA1 inhibitor

RIAMQV SEQ ID NO: 12 TRPA1 inhibitor

VGDIAEVQKHAS SEQ ID NO: 33 TRPA1 inhibitor

VGDIAEVQKHASLKRIAMQV SEQ ID NO: 34 TRPA1 inhibitor

Table 2

The peptides of the invention or their functionally equivalent variants have the ability to inhibit the TRPV1, TRPM8 and / or TRPA1 receptors. He corresponding TRP receptor, as used herein, refers to a mammalian derived receptor, such as human, monkey, rat, mouse, dog, bovine species, rabbit and the like, of birds, fish or other animal . The amino acid sequence of TRPV1 is registered in the GenBank database under accession number CAB89866 (Homo sapiens), that of TRPM8 under accession number ACQ66098 (Homo sapiens) and that of TRPA1 under accession number AC022867 {Homo sapiens).

The term "functionally equivalent variant", as used in the present invention, means all those peptides derived from the sequence of the peptides of the invention by modification, insertion and / or elimination of one or more amino acids, provided and when the function of said peptide is maintained at least 20%, at least 50%, at least 80%, with respect to the function of the corresponding peptide of the invention without modifications, insertions and / or deletions. In a particular embodiment, the function of the peptide of the invention and its functionally equivalent variants is determined by measuring its inhibitory capacity of the activity of the TRP receptors, specifically by measuring the inhibition of calcium flow through the receptor. Suitable methods for determining the ability of the functionally equivalent peptide or variant to inhibit TRP activity, are known to the person skilled in the art and include, for example and without limitation, the method described in the examples of the present invention for the TRPV1 receptor, based on monitoring intracellular Ca ²⁺ signals in neuroblastoma cells expressing TRPV1 (SH-SY5Y-TRPV1). Activation of the TRPV1 receptor by treatment with capsaicin involves the opening of the ionic channel of the receptor expressed in said cells and the consequent increase in the concentration of intracellular calcium. However, when a TRPV1 receptor inhibitor peptide or a functionally equivalent variant is added, the intracellular calcium concentration decreases with respect to the cells untreated with the inhibitor peptide or a functionally equivalent variant. The same would apply to the other two thermoreceptors. In the examples of the present invention, for example and without limitation, the measurement of the capacity of inhibition of TRPM8 by the peptides of the invention in HEK293 cells expressing TRPM8 and whose receptors are activated by treatment with menthol is described, and the measurement of the inhibition of TRPA1 by the peptides of the invention in CHO cells expressing TRPA1 and whose receptors are activated by treatment with cinnamaldehyde. A peptide of the invention or a functionally equivalent variant it is considered to inhibit the activity of TRPV1, TRPM8 and / or TRPA1 if it inhibits its function, that is, if the activity of TRPV1, TRPM8 and / or TRPA1 is decreased by at least 15%, at least 20%, at least one 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100%, with respect to that of cells expressing the untreated TRP receptor with the inhibitor peptide.

Variants suitable for use in the present invention include those showing at least 25%, at least 40%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at at least 96%, at least 97%, at least 98% or at least 99% sequence identity with respect to the peptide sequence indicated above. The degree of identity between two amino acid sequences can be determined by conventional methods, for example, by standard sequence alignment algorithms known in the state of the art, such as, for example, BLAST (AltschuI SF et al. Basic Local Alignment Search Tool J Mol Biol. 1990 Oct 5; 215 (3): 403-10).

In the context of the present invention the modification of the peptide of the invention to generate a functionally equivalent variant is carried out by substituting one or more amino acids of the peptide of the invention with one of its corresponding equivalent amino acids in terms of their properties. The following amino acids are considered equivalent in their properties: glutamic acid (E) and aspartic acid (D); threonine (T) and serine (S); valine (V), leucine (L) and isoleucine (I); asparagine (N) and glutamine (Q); lysine (K), arginine (R) and histidine (H) and finally the aromatic amino acids phenylalanine (F), tryptophan (W) and tyrosine (Y) - The person skilled in the art will understand that the amino acid sequences at which referenced in this description may be chemically modified, for example, by chemical modifications that are physiologically relevant, such as phosphorylation, acetylation, amidation, pegylation, or palmitoylation, among others.

The peptides of the present invention and their functionally equivalent variants may exist as stereoisomers or mixtures of stereoisomers; for example, the amino acids that compose them can have an L-, D-, or be racemic configuration independently of each other. Therefore, it is possible to obtain isomeric mixtures as well as racemic or diastereomeric mixtures, or pure diastereomers or pure enantiomers, depending on the number of asymmetric carbons and what isomers or isomeric mixtures are present. Preferred structures of the peptides of the invention and their functionally equivalent variants are pure isomers, that is, enantiomers or diastereomers.

Also within the scope of the present invention are the cosmetically or pharmaceutically acceptable salts of the peptides provided by this invention. The term "cosmetically or pharmaceutically acceptable salts" means a salt recognized for use in animals and more particularly in humans, and includes salts used to form base addition salts, whether inorganic, for example and without limitation, lithium, sodium, potassium, calcium, magnesium, manganese, copper, zinc or aluminum, among others, whether organic, for example and without limitation, ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, arginine, lysine, histidine or piperazine among others, or acid addition salts, whether organic, for example and without limitation, acetate, citrate, lactate, malonate, maleate, tartrate, fumarate, benzoate, aspartate, glutamate, succinate, oleate, trifluoroacetate, oxalate, pamoate or gluconate between others, or inorganic, such as for example and without limitation chloride, sulfate, borate or carbonate among others. The nature of salt is not critical, as long as it is cosmetically or pharmaceutically acceptable. Cosmetically or pharmaceutically acceptable salts of the peptides of the invention can be obtained by conventional methods, well known in the state of the art [Berge S.M. et al. (1977) J. Pharm. Sci. 66: 1-19].

Methods for preparing the peptides of the invention

The synthesis of the peptides of the invention, their functionally equivalent variants, their stereoisomers or their cosmetically or pharmaceutically acceptable salts can be carried out according to conventional methods, known in the state of the art, such as for example by solid phase peptide synthesis methods [ Stewart JM and Young JD (1984) "Solid Phase Peptide Synthesis, 2nd edition" Pierce Chemical Company, Rockford, Illinois; Bodanzsky M. and Bodanzsky A. (1994) "The practice of Peptide Synthesis" Springer Verlag, Berlin; Lloyd-Williams P. et al. (1997) "Chemical Approaches to the Synthesis of Peptides and Proteins" CRC, Boca Raton, FL, USA], solution synthesis, a combination of solid-phase and solution synthesis methods or enzymatic synthesis [Kullmann W. (1980) J.Biol.Chem. 255: 8234-8238]. Peptides can also be obtained by fermentation of a bacterial strain, modified or not by genetic engineering with the aim of producing the desired sequences, or by controlled hydrolysis of proteins of animal or vegetable origin, preferably vegetable, that release peptide fragments containing at least the desired sequence.

By way of illustration, a method of obtaining the peptides of the invention and their functionally equivalent variants comprises the steps of:

- coupling of an amino acid, with the protected end / V-terminal and the free C-terminal end, onto an amino acid with the free end / V-terminal and the protected C-terminal end or attached to a solid support; - Elimination of the end / V-terminal protective group;

-repetition of the coupling sequence and elimination of the end / V-terminal protecting group until the desired peptide sequence is obtained;

- removal of the protective group from the C-terminal end or excision of the solid support

Preferably, the C-terminal end is attached to a solid support and the process is carried out in solid phase and, therefore, comprises the coupling of an amino acid with the protected / V-terminal end and the free C-terminal end on an amino acid. with the free / V-terminal end and the C-terminal end attached to a polymeric support; removal of the end / V-terminal protecting group; and repeating this sequence as many times as necessary to obtain the peptide of the desired length, finally followed by the cleavage of the synthesized peptide from the original polymeric support.

The functional groups of the amino acid side chains are conveniently maintained protected with temporary or permanent protecting groups throughout the synthesis, and can be simultaneously or orthogonally deprotected from the polymeric peptide cleavage process.

Alternatively, solid phase synthesis can be performed by a convergent strategy by coupling a peptide on the polymeric support or on a peptide or amino acid previously attached to the polymeric support. Convergent synthesis strategies are widely known to experts in the field and are described in Lloyd-Williams P. et al. (1993) Tetrahedron 49: 1 1065-1 1 133. The method may comprise the additional steps of deprotection of the / V-terminal and / or C-terminal ends and / or cleavage of the polymeric support peptide in the same order, using standard procedures and conditions known in the art, after which they can be modified the functional groups of said ends. Optional modification of the / V-terminal and / or C-terminal ends can be performed with the peptide sequence of the peptide of the invention anchored to the polymeric support or once the peptide has been cleaved from the polymeric support.

One skilled in the art will readily understand that the deprotection / cleavage stages of the C-terminal and / V-terminal ends and their subsequent derivatization can be performed in the same order, according to procedures known in the art.

The term "protecting group" refers to a group that blocks an organic functional group and that can be removed under controlled conditions. The protecting groups, their relative reactivities and the conditions in which they remain inert are known to the person skilled in the art.

Examples of representative protecting groups for the amino group are amides, such as amide acetate, amide benzoate, amide pivalate; carbamates, such as benzyloxycarbonyl (Cbz or Z), 2-chlorobenzyl (CIZ), para-nitrobenzyloxycarbonyl (pNZ), íerc-butyloxycarbonyl (Boc), 2,2,2-trichloroethyloxycarbonyl (Troc), 2- (trimethylsilyl) ethyloxycarbonyl ( Teoc), 9-fluorenylmethyloxycarbonyl (Fmoc) or allyloxycarbonyl (Alloc), trityl (Trt), methoxytrityl (Mtt), 2,4-dinitrophenyl (Dnp), / V- [1 - (4,4-dimethyl-2,6 -dioxocyclohex-1-iridene) ethyl (Dde), 1 - (4,4-dimethyl-2,6-dioxo-cyclohexylidene) -3-methyl-butyl (ivDde), 1 - (1 -adamantil) -1-methylethoxy -carbonyl (Adpoc), among others; preferably, Boc or Fmoc.

Examples of representative protecting groups for the carboxyl group are esters, such as the butyl ester (tBu), allyl ester (All), triphenylmethyl ester (trityl ester, Trt), cyclohexyl ester (cHx), benzyl ester (Bzl), orio-nitrobenzyl ester, para-nitrobenzyl ester, para-methoxybenzyl ester, trimethylsilylethyl ester (TMS), 2-phenylisopropyl ester, fluorenylmethyl ester (Fm), 4- ( / V- [1 - (4,4-dimethyl-2,6-dioxcyclohexylidene) -3-methylbutyl] amino) benzyl (Dmab), among others; Preferred protecting groups of the invention are the esters of All, tBu, cHx, Bzl and Trt. The side chains of the trifunctional amino acids can be protected during the synthetic process with temporary or permanent orthogonal protecting groups to the end-protecting / V-terminal and C-terminal protecting groups.

The arginine side chain is protected with a protective group selected from the group consisting of tosyl (Tos), 4-methoxy-2,3,6-trimethylbenzenesulfonyl (Mtr), Alloc, nitro, 2,2,4,6,7- pentamethyldihydrobenzofuran-5-sulfonyl (Pbf) and 2,2,5,7,8-pentamethylchroman-6-sulfonyl (Pmc), the lysine side chain is protected with a protective group selected from the group consisting of CIZ, Z, 4- nitroZ, Fmoc, Boc, acetyl (Ac), Cough, Dde, ivDde, Dnp, Mtt and Alloc, the side chains of aspartic acid and glutamic acid are protected with a protective group selected from the group consisting of Trt, Bzl, cHx, tBu and All, the tyrosine side chain is protected with a protective group selected from the group consisting of 2-bromobenzyloxycarbonyl (2-BrZ), Boc, All, 2,6-dichlorobenzyloxycarbonyl (2,6-diCIZ), Bzl and tBu , the methionine side chain is used protected with the sulfoxide group or is used unprotected, the histidine side chain is protected with a protective group selected from the group po formed by Tos, Dnp, methyl (Me), Boc, benzyloxymethyl (Bom), Bzl, Fmoc, Mts, Trt and Mtt, the tryptophan side chain is protected with a protective group selected from the group formed by formyl (For), Boc and mesitylene-2-sulfonyl (Mts) or is used without protection, the asparagine and glutamine side chain is protected with a protective group selected from the group consisting of Trt, Mtt and β-xanthyl (Xan) or is used without protection, and the threonine and serine side chain is protected with a protective group selected from the group consisting of tBu, Bzl, Trt and Ac.

Cosmetic or pharmaceutical compositions of the invention

In another aspect, the invention relates to a cosmetic or pharmaceutical composition, hereinafter cosmetic or pharmaceutical composition of the invention, comprising at least one of the peptides of the invention or a functionally equivalent variant, its stereoisomers, mixtures thereof and / or its cosmetically or pharmaceutically acceptable salts, together with at least one cosmetic or pharmaceutically acceptable adjuvant.

The peptides of the present invention have a variable water solubility, depending on the nature of their sequence or the possible modifications in the / V-terminal and / or C-terminal ends that they present. Thus, the peptides of the present invention can be incorporated into the compositions by aqueous solution, and those that are not soluble in water can be solubilized in solvents. conventional cosmetics or pharmaceutically acceptable such as, for example and without limitation, ethanol, propanol, isopropanol, propylene glycol, glycerin, butylene glycol or polyethylene glycol or any combination thereof.

The cosmetic or pharmaceutically effective amount of the peptides of the invention to be administered, as well as their dosage, will depend on numerous factors, including the age, patient's condition, the nature or severity of the disorder or disease to be treated or prevented, the route and frequency of administration and the particular nature of the peptides to be used.

By "cosmetic or pharmaceutically effective amount" is meant a non-toxic but sufficient amount of the peptide or peptides of the invention to provide the desired effect. The peptides of the invention are used in the cosmetic or pharmaceutical composition of the present invention at cosmetic or pharmaceutically effective concentrations to achieve the desired effect; preferably, with respect to the total weight of the composition, between 0.00000001% (by weight) and 20% (by weight); preferably between 0.000001% (by weight) and 15% (by weight), more preferably between 0.00001% (by weight) and 10% (by weight) and even more preferably between 0.001% (by weight) and 5% (by weight).

The peptides of the invention or their functionally equivalent variants, their stereoisomers, mixtures thereof and / or their cosmetically or pharmaceutically acceptable salts, can also be incorporated into vehiculization systems and / or cosmetic or pharmaceutical sustained release systems.

The term "vehiculization systems" refers to a diluent, adjuvant, excipient or vehicle with which the peptide of the invention is administered. Such cosmetic or pharmaceutical vehicles may be liquids, such as water, oils or surfactants, including those of petroleum, animal, vegetable or synthetic origin, such as, for example and without limitation, peanut oil, soybean oil, mineral oil, sesame oil , castor oils, polysorbates, sorbitan esters, ether sulfates, sulfates, betaines, glycosides, maltósidos, fatty alcohols, nonoxinoles, poloxamers, polyoxyethylene, polyethylene glycols, dextrose, glycerol, digitonin and the like. A person skilled in the art knows the diluents, adjuvants or excipients that can be used in the different vehicle systems in which the peptide of the invention can be administered.

The term "sustained release" is used in the conventional sense referring to a system of vehiculization of a compound that provides gradual release of said compound over a period of time and preferably, but not necessarily, with relatively constant levels of compound release over a period of time.

Examples of vehiculization or sustained-release systems include, without limitation, liposomes, mixed liposomes, oleosomes, niosomes, etosomes, miliparticles, microparticles, nanoparticles and solid lipid nanoparticles, nanostructured lipid supports, sponges, cyclodextrins, vesicles, micelles, mixed micelles of surfactants, mixed phospholipid-surfactant micelles, microspheres, microspheres and nanospheres, lipospheres, microcapsules, microcapsules and nanocapsules, as well as in microemulsions and nanoemulsions, which can be added to achieve greater penetration of the active ingredient and / or improve the pharmacokinetic properties and pharmacodynamics thereof. Preferred vehiculization or sustained-release systems are liposomes, mixed micelles phospholipid tesioactive and microemulsions, more preferably water-in-oil microemulsions with internal reverse micelle structure.

Sustained release systems can be prepared by methods known in the state of the art, and the compositions containing them can be administered, for example, by topical or transdermal administration, including adhesive patches, non-adhesive patches, occlusive patches and microelectric patches, or by systemic administration, such as for example and without limitation by oral or parenteral route, including nasal, rectal, implantation or subcutaneous injection, or direct implantation or injection into a particular part of the body, and preferably should release a relatively quantity constant of the peptides of the invention. The amount of peptide contained in the sustained release system will depend, for example, on the site of administration, the kinetics and duration of release of the peptide of the invention, as well as the nature of the disorder or disease to be treated or prevented.

The peptides of the present invention can also be adsorbed on solid organic polymers or solid mineral supports such as for example and without limitation talc, bentonite, silica, starch or maltodextrin among others.

Compositions containing the peptides of the invention or their functionally equivalent variants, their stereoisomers, mixtures thereof and / or their cosmetically or pharmaceutically acceptable salts, can also be incorporated into tissues, non-woven fabrics and products. toilets that are in contact directly with the skin, so that they release the peptides of the invention either by biodegradation of the tissue anchoring system, non-woven fabric or medical device or by their friction with the body, by body moisture, by the Skin pH or body temperature. Also, tissues and non-woven fabrics can be used to make garments that are in direct contact with the body.

Examples of tissues, non-woven fabrics, garments, medical devices and means of immobilization of the peptides to them, among which are the vehiculization systems and / or the sustained release systems described above, can be found described in the literature. and are known in the state of the art [Schaab CK (1986) HAPPI May 1986; Nelson G. (2002) Int. J. Pharm. 242: 55-62; "Biofunctional Textiles and the Skin" (2006) Curr. Probl. Dermatol v.33, Hipler U.C. and Elsner P., eds. S. Karger AG, Basel, Switzerland; Malcom R.K. et al. (2004) J. Cont. Relay 97: 313-320]. Fabrics, non-woven fabrics, garments and sanitary products preferred are bandages, gauze, T-shirts, socks, socks, underwear, girdles, gloves, diapers, compresses, dressings, bedspreads, wipes, adhesive patches, non-adhesive patches, occlusive patches , microelectric patches and / or facial masks.

The cosmetic or pharmaceutical compositions containing the peptides of the invention or their functionally equivalent variants, their stereoisomers, mixtures thereof and / or their cosmetically or pharmaceutically acceptable salts, can be used in different types of topically or transdermally applied compositions that will optionally include the cosmetically or pharmaceutically acceptable excipients necessary for the formulation of the desired administration form. One skilled in the art knows the different excipients that can be used in cosmetic or pharmaceutical compositions containing the peptides of the invention.

Compositions of topical or transdermal application can be presented in any solid, liquid or semi-solid formulation, such as, for example and without limitation, creams, multiple emulsions such as, for example and without limitation, oil and / or silicone emulsions in water, emulsions of water in oil and / or silicone, emulsions of the water / oil / water or water / silicone / water type and emulsions of the oil / water / oil or silicone / water / silicone type, anhydrous compositions, aqueous dispersions, oils, milks, balms, foams, lotions, gels, cream gels, hydroalcoholic solutions, hydro-glycol solutions, hydrogels, liniments, serums, soaps, shampoos, conditioners, serums, polysaccharide films, ointments, mousses, ointments, powders, bars, pencils and vaporizers or aerosols ("sprays"), including permanence or "leave on" formulations and rinse or rinse formulations -off ". These formulations of topical or transdermal application can be incorporated by means of techniques known to those skilled in the art to different types of solid accessories such as for example and without limitation bandages, gauze, T-shirts, socks, stockings, underwear, girdles, gloves , diapers, compresses, dressings, bedspreads, wipes, adhesive patches, non-adhesive patches, occlusive patches, microelectric patches or facial masks, or can be incorporated into different makeup line products such as makeup funds, such as fluid makeup funds and compact makeup funds, make-up lotions, cleansing milks, dark circles, eyeshadow, lipstick, lip balm, lip gloss and powder among others.

The cosmetic or pharmaceutical compositions of the invention may include agents that increase the percutaneous absorption of the peptides of the invention, such as and without limitation, dimethylsulfoxide, dimethylacetamide, dimethylformamide, surfactants, azone (1-dodecylazacycloheptan-2-one), alcohol , urea, ethoxyglycol, acetone, propylene glycol or polyethylene glycol among others. Likewise, the cosmetic or pharmaceutical compositions object of the present invention can be applied in the local areas to be treated by iontophoresis, sonophoresis, electroporation, microelectric patches, mechanical pressure, osmotic pressure gradient, occlusive cure, microinjections or needleless injections by pressure, such as for example, oxygen pressure injections, or any combination thereof, to achieve greater penetration of the peptide of the invention. The area of application will be determined by the nature of the disorder or disease to be treated or prevented.

Likewise, cosmetic or pharmaceutical compositions containing the peptides of the invention or their functionally equivalent variants, their stereoisomers or their cosmetically or pharmaceutically acceptable salts can be used in different types of formulations for oral administration, preferably in the form of cosmetics or oral drugs, such as and without limitation in capsules, including gelatin capsules, soft capsules, hard capsules, tablets, including sugar-coated tablets, tablets, pills, powders, granulated forms, chewing gums, solutions, suspensions, emulsions, syrups, elixirs, polysaccharide films, jellies or jellies, as well as in any other presentation known to an expert in the field. In a particular embodiment, the peptides of the invention can be incorporated into any form of functional food or fortified food, such as and without limitation in dietary bars or in compact or non-compact powders. Said powders can be solubilized in water, soda, dairy products, soy derivatives or incorporated into dietary bars. The peptides of the invention can be formulated with the usual excipients and adjuvants for oral compositions or food supplements, such as and without limitation, fatty components, aqueous components, humectants, preservatives, texturizing agents, flavors, aromas, antioxidants and common dyes in the food sector.

The cosmetic or pharmaceutical compositions containing the peptides of the invention or their functionally equivalent variants, their stereoisomers, mixtures thereof and / or their cosmetically or pharmaceutically acceptable salts can be administered in addition to topically or transdermally, by any other type of route. appropriate, for example orally or parenterally, for which they will include the pharmaceutically acceptable excipients necessary for the formulation of the desired administration form. In the context of the present invention, the term "parenteral" includes nasal, atrial, ophthalmic, rectal, urethral, vaginal, subcutaneous, intradermal, intravascular injections such as intravenous, intramuscular, intraocular, intravitreal, intracorneal, intraspinal, intramedullary, intracranial, intracervical, intracerebral, intrameningeal, intraarticular, intrahepatic, intrathoracic, intratracheal, intrathecal and intraperitoneal, as well as any other similar injection or infusion technique. One skilled in the art knows the different ways in which cosmetic or pharmaceutical compositions containing the peptides of the invention can be administered.

Among the cosmetic or pharmaceutically acceptable adjuvants contained in the cosmetic or pharmaceutical compositions described in the present invention are the additional ingredients commonly used in cosmetic or pharmaceutical compositions, such as for example and without limitation, other anti-inflammatory and / or analgesic agents, other antipruritic agents, calming agents, anesthetic agents, inhibitors of aggregation of acetylcholine receptors, inhibitors of muscle contraction, anticholinergic agents, elastase inhibitors, matrix metalloprotease inhibitors, stimulating agents or inhibitors of the synthesis of melanin, bleaching or depigmenting agents, propigmentation agents, self-tanning agents, agents anti-aging agents, NO-synthase inhibitors, 5-reductase inhibitors, lysyl- and / or prolyl-hydroxylase inhibitors, antioxidant agents, free radical capture and / or atmospheric anti-pollution agents, carbonyl reactive species capture agents, agents antiglication, antihistamine agents, antiviral agents, antiparasitic agents, emulsifying agents, emollients, organic solvents, liquid propellants, skin conditioners, moisturizers, moisture-retaining substances, alpha hydroxy acids, beta hydroxy acids, hydrating agents, hydrolytic epidermal enzymes, vitamins, amino acids, proteins , pigments or dyes, dyes, biopolymers, gelling polymers, thickening agents, surfactants, softening agents, emulsifiers, binding agents, preservatives, anti-wrinkle agents, agents capable of diminishing or treating the bags under the eyes, exfoliating agents, antimicrobial agents, age Antifungal agents, fungistatic agents, bactericidal agents, bacteriostatic agents, agents that stimulate the synthesis of dermal or epidermal macromolecules and / or capable of inhibiting or preventing their degradation, agents that stimulate collagen synthesis, agents that stimulate elastin synthesis, agents Decorin synthesis stimulators, laminin synthesis stimulating agents, defensin synthesis stimulating agents, aquaporin synthesis stimulating agents, hyaluronic acid synthesis stimulating agents, fibronectin synthesis stimulating agents, stimulating agents of the synthesis of sirtuins, agents that stimulate the synthesis of heat shock proteins, agents that stimulate the synthesis of lipids and components of the stratum corneum, ceramides, fatty acids, agents that inhibit collagen degradation, agents that inhibit degradation of elastin, serine protease inhibiting agents such as cathepsin G, fibroblast proliferation stimulating agents, keratinocyte proliferation stimulating agents, adipocyte proliferation stimulating agents, melanocyte proliferation stimulating agents, keratinocyte differentiation stimulating agents, adipocyte differentiation stimulating agents, acetylcholinesterase inhibiting agents, dermo-relaxant agents, glycosaminoglycan synthesis stimulating agents, antihyperkeratosis agents, comedolytic agents, antipsoriasis agents, DNA repair agents, DNA protective agents, stabilizers, treatment agents and / or care of sensitive skin, firming agents, anti-stretch agents, astringent agents, sebum production regulating agents, agents lipolytic or lipolysis stimulants, anti-cellulite agents, antiperspirant agents, healing stimulating agents, healing aids, re-epithelialising agents, re-epithelializing agents, cytokine growth factors, capillary circulation agents and / or microcirculation, angiogenesis stimulating agents, vascular permeability inhibiting agents, venotonic agents, agents that act on cell metabolism, agents intended to improve dermis-epidermis binding, hair growth inducing agents, agents hair growth inhibitors or retardants, hair loss retardants, preservatives, perfumes, chelating agents, plant extracts, essential oils, marine extracts, agents from a biofermentation procedure, mineral salts, cell extracts, sunscreens and photoprotective agents of organic or mineral nature active against ultraviolet A and / or B rays, or mixtures thereof, provided they are physically and chemically compatible with the other components of the composition and especially with the peptides of the invention. Also, the nature of said additional ingredients should not unacceptably alter the benefits of the peptides of the present invention. The nature of said additional ingredients may be synthetic or of natural origin, such as plant extracts, or come from a biotechnological process or a combination of a synthetic procedure and a biotechnological process. Additional examples can be found described in CTFA International Cosmetic Ingredient Dictionary & Handbook, 12th Edition (2008). In the context of the present invention, biotechnological method is understood as any procedure that produces the active substance, or part thereof, in an organism, or in a part thereof.

A further aspect of the present invention relates to a cosmetic or pharmaceutical composition comprising a cosmetic or pharmaceutically effective amount of at least one peptide of the invention or a functionally equivalent variant, its stereoisomers, mixtures thereof and / or its cosmetic salts. or pharmaceutically acceptable, and also a cosmetic or pharmaceutically effective amount of at least one anti-wrinkle agent and / or anti-aging agent selected, without limitation, from the group formed by the extracts of Vitis vinifera, Rosa canina, Turmeric longa, Iris pallida, Theobroma cacao , Ginkgo biloba, Leontopodium alpinum or Dunaliella salina among others or at least one synthetic compound or product of biotechnological origin that is an agent wrinkle and / or antiaging agent such as and not limited Matrixyl ^® [INCI: Palmitoyl Pentapeptide-4], Matrixyl 3000 ^® [INCI: Palmitoyl Tetrapeptide-7, Palmitoyl Oligopeptide], Essenskin ™ [INCI: calcium hydroxymethionine] Renovage [ INCI: teprenone] or Dermaxyl ^® [INCI: Palmitoyl Oligopeptide] marketed by Sederma, Vialox ^® [INCI: Pentapeptide-3], Syn ^® -Ake ^® [INCI: Dipeptide Diaminobutyroyl Benzylamide Diacetate], Syn ^® -Coll [INCI: Palmitoyl Tripeptide -5], Phytaluronate [INCI: Locust Bean (Ceratonia Siliqua) Gum] or Preregen ^® [INCI: Glycine Soy (Soybean) Protein, Oxido Reductases] marketed by Pentapharm / DSM, Myoxinol ™ [INCI: Hydrolyzed Hibiscus Esculentus Extract], Syniorage ™ [INCI: Acetyl Tetrapeptide-1 1], Dermican ™ [INCI: Acetyl Tetrapeptide-9] or DN-AGE ™ LS [INCI: Cassia Alata leaf Extract] marketed by Laboratoires Sérobiologiques / Cognis, Algisum C ^® [INCI: Methylsilanol Mannuronate ] or Hydroxyprolisilane CN ^® [ INCI: Methylsilanol Hydroxyproline Aspartate] marketed by Exsymol, Argireline ^® [INCI: Acetyl Hexapeptide-8] (Acetyl Hexapeptide-8), SNAP-7 [INCI: Acetyl Heptapeptide-4] (Acetyl Heptapeptide-4), SNAP-8 [INCI : Acetyl Octapeptide-3] (Acetyl Octapeptide-3), Leuphasyl ^® [INCI: Pentapeptide-18] (Pentapeptide-18), Inyline ™ [INCI: Acetyl Hexapeptide-30] (Acetyl Hexapeptide-30), Aldenine ^® [INCI: Hydrolized wheat protein, hydrolized soy protein, Tripeptide-1] (Hydrolyzed Wheat Protein, Hydrolyzed Soy Protein, Tripeptide-1), Preventhelia ^® [INCI: Diaminopropionoyl Tripeptide-33] (Diaminopropionoil Tripeptide-33), Decorinyl ^® [INCI: Tripeptide-10 Citrulline] (Tripeptide-10 Citrulline), Trylagen ^® [INCI: Pseudoalteromonas Ferment Extract, Hydrolyzed Wheat Protein, Hydrolyzed Soy Protein, Tripeptide-10 Citrulline, Tripeptide-1] (Pseudoalteromonas Ferment Extract, Hydrolyzed Wheat Protein Hydrolyzed Soy Protein, Tripeptide-10 Citrulline, Tripeptide-1), Eyeseryl ^® [INCI: Acetyl Tetrapeptide-5] (Acetyl Tetrapeptide-5), Peptide AC29 [INCI: Acetyl Tripeptide-30 Citrulline] (Acetyl Tripeptide-30 Citrulline), Relistase ^® [INCI: Acetylarginyltriptophyl Diphenylglycine] ( Acetylarginyltryptophyl Diphenylglycine), Thermostressine ^® [INCI: Acetyl Tetrapeptide-22] (Acetyl Tetrapeptide-22), Lipochroman-6 [INCI: Dimethylmethoxy chromanol] (Dimetilmetoxi chromanol), Chromabright ™ [INCI: Dimethylmethoxy chromanyl Palmitate] (Dimetilmetoxi chromanyl Palmitate), Antarcticine ^® [INCI: Pseudoalteromonas Ferment Extract] (Pseudoalteromonas Ferment Extract), dGIyage ™ [INCI: Lysine HCI, Lecithin, Tripeptide-9 Citrulline] (Lysine HCI, Lecithin, Tripeptide-9 Citrulline) or Vilasteneine [INCI]: Vilastene ™ [INCI HCI, Lecithin, Tripeptide-10 Citrulline] (Lysine HCI, Lecithin, Tripeptide-10 Citrulline) marketed by Lipotec, Kollaren ^® [INCI: Tripeptide-1, Dextran] marketed by Institut Europeen de Biologie Cellulaire, Collaxyl ^® IS [INCI: Hexapeptide-9], Laminixyl IS ™ [INCI: Heptapeptide], Orsirtine ™ GL [INCI: Oryza Sativa (Rice) Extract], D'Orientine ™ IS [ INCI: Phoenix Dactylifera (Date) Seed Extract], Phytoquintescine ™ [INCI: Einkorn (Triticum Monococcum) Extract] or Quintescine ™ IS [INCI: Dipeptide-4] marketed by Vincience / ISP, BONT-L-Peptide [INCI: Palmitoyl Hexapeptide -19] marketed by Infinitec Assets, Deepaline ™ PVB [INCI: Palmitoyl hydrolyzed Wheat Protein] or Sepilift ^® DPHP [INCI: Dipalmitoyl Hydroxyproline] marketed by Seppic, Gatuline ^® Expression [INCI: Acmella olerácea Extract], Gatuline ^® In-Tense [ INCI: Spilanthes Acmella Flower Extract] or Gatuline ^® Age Defense 2 [INCI: Juglans Regia (Walnut) Seed Extract] marketed by Gattefossé, Thalassine ™ [INCI: Algae Extract] marketed by Biotechmarine, ChroNOline ™ [INCI: Caprooyl Tetrapeptide-3] o Thymulen-4 [INCI: Ace tyl Tetrapeptide-2] marketed by Atrium Innovations / Unipex Group, EquiStat [INCI: Pyrus Malus Fruit Extract, Glycine Soybean Seed Extract] or Juvenesce [INCI: Ethoxydiglicol and Caprylic Triglycerid, Retinol, Ursolic Acid, Phytonadione, lllettat] marketed Engelhard / BASF, Ameliox [INCI: Carnosine, Tocopherol, Silybum Marianum Fruit Extract] or PhytoCelITec Malus Domestica [INCI: Malus Domestica Fruit Cell Culture] marketed by Mibelle Biochemistry, Bioxilift [INCI: Pimpinella Anisum Extract] or SMS Anti-Wrinkle ^® INCI: Annona Squamosa Seed Extract] marketed by Silab, calcium channel antagonists such as, for example and without limitation, alverin, manganese or magnesium salts, certain secondary or tertiary amines, retinol and its derivatives, idebenone and its derivatives, Coenzyme Q10 and its derivatives, boswellic acid and its derivatives, GHK and its derivatives and / or salts, carnosine and its derivatives, DNA repair enzymes such as and without limitation photoliase or T4 endonuclease V, or chloride channel agonists among others, or mixtures thereof.

A further aspect of the present invention relates to a cosmetic or pharmaceutical composition comprising a cosmetic or pharmaceutically effective amount of at least one peptide of the invention or a functionally equivalent variant, its stereoisomers, mixtures thereof and / or its cosmetic salts. or pharmaceutically acceptable, and also a cosmetic or pharmaceutically effective amount of at least one natural extract or essential oil that is an anti-inflammatory and / or analgesic agent such as for example and without limitation, madecasoside, equinacin, amaranth seed oil, oil sandalwood, peach leaf extract, Aloe vera extracts, Arnica montana, Artemisia vulgaris, Asarum maximum, Calendula officinalis, Capsicum, CENTIPEDA CUNNINGHAMII, Chamomilla recutita, Crinum asiaticum, Hamamelis virginiana, procumbens Harpagophytum, Hypericum períoratum, Lilium candidum, Malva sylvestris, Melaleuca alternifolia, Origanum majorana, Origanum vulgare, Prunus laurocerasus, Rosmarinus officialis, Salix alba, Silybum marianum, Tanacetum parthenium, Thymus vulgaris, Uncaria guianensis or Vaccinum myrtillus among others or in addition at least one synthetic compound or product of biotechnological origin that is an anti-inflammatory agent and / or analgesic as for example and without limited sense furoate mometasone and prednisolone, non-steroidal anti-inflammatories including cyclooxygenase or lipoxygenase inhibitors, benzidamine, acetylsalicylic acid, rosmarinic acid, ursolic acid, derivatives of glycyrrhizinate, obisabolol, zenne and analogues, sericoside, ruscogenin, escin, escolin, rutin and analogues clobetas ol, dexamethasone, prednisone, acetaminophen / acetaminophen, amoxiprin, benorilate, choline salicylate, diflunisal, phalamine, methyl salicylate, magnesium salicylate, olsalacina, sulfasalacina, salsalate, diclofenac, aceclofenac, acemetacinate, zametacinate, acemetacinate, zethecinazine, acemetacinate, zethecinate oxametacin, proglumetacin, sulindac, tolmetin, ibuprofen, dexibuprofen, carprofen, fenbufen, fenoprofen, flurbiprofen, ketoprofen, dexketoprofen, nitroflurbiprofen, ketorolac, loxoprofen, naproxen, miroprofen, oxaprozin, pranoprofen, tiaprofenic acid, suprofen, mefenamic acid, meclofenamate, meclofenamic acid , flufenamic acid, tolfenamic acid, nabumetone, phenylbutazone, azapropazone, clofezone, kebuzone, metamizole, mofebutazone, oxyphenbutazone, phenazone, sulfinpyrazone, piroxicam, lornoxicam, meloxicam, tenoxicam, celecoxib, etoricoxib, lumiracoxib, parecoxib, rofecoxib, valdecoxib, nimesulide, naproxcinod , flufenisal, fluprocuazone or licofelone; morphine, codeine, oxycodone, hydrocodone, diamorphine, pethidine, tramadol, brupenorphine, benzocaine, lidocaine, chloroprocaine, tetracaine, procaine, anticonvulsants, tricyclic antidepressants, amitriptyline, carbamazepine, gabapentin, pregabalimine, pantenolotodium, panthenol, panthenol cyclopirox olamine, nordihydroguaarretic acid, Neutrazen ™ [INCI: Water, Butylene Glycol, Dextran, Palmitoyl Tripeptide-8] marketed by Atrium Innovations / Unipex Group, Meliprene ^® [INCI: Dextran, Acetyl Heptapeptide-1] marketed by Institui Européula de Biologéire de Biolog / Unipex Group, Skinasensyl ™ [INCI: Acetyl Tetrapeptide-15] marketed by Laboratoires Sérobiologiques / Cognis, SymSitive ^® 1609 [INCI: 4-t-Butylcyclohexanol] marketed by Symrise, Symbiocell ™ [INCI: Extract from Cestrum Latifolium] marketed by BASF , Gatuline ^® Derma-Sensitive [INCI: Octyldodecyl Myristate, Capparis Spinosa Fruit Extract] marketed by Gattefossé, MAXnolia [INCI: Magnolia Officinalis Bark Extract, Vitis Vinifera / Vitis Vinifera (Grape) Seed Extract, Tocopherol] marketed by Mibelle, coenzyme Q10 or ethers, among others .

A further aspect of the present invention relates to a cosmetic or pharmaceutical composition comprising a cosmetic or pharmaceutically effective amount of at least one peptide of the invention or a functionally equivalent variant, its stereoisomers, mixtures thereof and / or its cosmetic salts. or pharmaceutically acceptable, and also a cosmetic or pharmaceutically effective amount of at least one natural extract or essential oil that is an antipruritic agent such as, for example and without limitation, extracts of Abelmoschus esculentus, Actaea alba, Aglaia odorata, Alkanna tinctoria, Althaea officinalis, Altingia excelsa, Andropogon virginicus, Aralia nudicaulis, Aralia racemosa, Mexican Argemone, Barleria prionitis, Camelia sinensis, Caesalpinia digyna, Campsis grandiflora, Carissa congesta, Carthamus oxyacantha, Cassia tora, Chrysantimicum, Clementum, Cymomatumum, Clementum, Crymomatum, Crymomatum, Crymomatum, Crymomatus Cuscuta reflexa, Diospyros pilgrim, E nicostema axillare, Hammamelis virginiana, Jatropha multifida, Lavandula officinalis, Lavandula latifolia, Liquidambar orientalis, Lithospermum officinale, Madhuca longifolia, Martynia annua, Medicago sativa, Michelia champaca, Mikania glomerata, Mimosa púdica, Oryza sativa, Phylalanthususus, Phaseoluslaususus , Pistacia vera, Polygonum hydropiper, Quercus ilex, Rauvolfia caffra, Ricinus communis, Rubus idaeus, Sagittaria sagittifolia, Sandoricum koetjape, Sapindus mukorossi, Schleichera oleosa, Sesbania grandiflora, Spondias dulcís, Tilia trangtaona, Tilia trichtaquula, Tilia trichtaquula, Tilia trichtamata Vaccaria pyramidata, Ventilago madraspatana, Veratrum album or Xanthium strumarium, among others, or at least one synthetic compound or product of biotechnological origin that is an antipruritic agent such as, for example, and with no limited sense mepyramine (pyrilamine), antazoline, diphenhydramine, carbinoxamine, doxylamine clemastine dimenhydrin to, pheniramine, chlorphenamine (chlorpheniramine), dexchlorpheniramine, brompheniramine, triprolidine, cyclizine, chlorcyclizine, hydroxyzine, medicine, cetirizine, levocetirizine, promethazine, alimemazine (trimeprazine), cyproheptadine, azatadine, ketotifen, acrivastine, astemizole, cetirizine, loratadine, desloratadine, mizolastine, terfenadine, fexofenadine, fexofenadine, azelastine, levocabastine, olopatadine, corticosteroids, cortisone, hydrocortisone, dexamethasone, prednisone, Neutrazen ™ [INCI: Water, Butylene Glycol, Dextran, Palmitoyl Tripeptide-8] marketed by Atrium Innovations / Unipex Group, Meliprene ^® [INCI: Dextran, Acetyl Heptapeptide-1] marketed by Institut Européen de Biologie Cellulaire / Unipex Group, Skinasensyl ™ [INCI: Acetyl Tetrapeptide-15] marketed by Laboratoires Sérobiolog / Cognis, SymSitive ^® 1609 [INCI: 4-t-Butylcyclohexanol] marketed by Symrise, Symbiocell ™ [INCI: Extract from Cestrum Latifolium] marketed by BASF, Gatuline ^® Derma-Sensitive [INCI: Octyidodecyl Myristate, Capparis Spinosa Fruit Extract] marketed by Gattefossé or MAXnolia [INCI: Magnolia Officinalis Bark Extract, Vitis ViniferaA / itis Vinifera (Grape) Seed Extract, Tocopherol] marketed by Mibelle among others.

Uses of peptides inhibiting TRP receptor activity

The peptides of the invention or their functionally equivalent variants, their stereoisomers, mixtures thereof and / or their cosmetically or pharmaceutically acceptable salts, are capable of inhibiting the activity of the TRP receptors, preferably the TRPV1, TRPM8 and / or TRPA1 receptors.

Therefore, the TRP receptor inhibitor peptides of the invention or their functionally equivalent variants, their stereoisomers, mixtures thereof and / or their cosmetically or pharmaceutically acceptable salts, can be used for the treatment and / or prevention of disorders and / or diseases such as pain, inflammation, pruritus, diseases and / or respiratory disorders and / or diseases and / or disorders associated with calcium imbalances.

Thus, in another aspect, the invention relates to the use of at least one peptide selected from the group consisting of:

(i) peptide comprising the SEO ID NO: 1 sequence or a functionally equivalent variant, where the length of said peptide is equal to or less than 25 amino acids and where the asparagine of the SEO ID NO: 1 sequence remains unchanged;

(ii) peptide comprising the SEO ID NO: 2 sequence or a functionally equivalent variant, wherein the length of said peptide is equal to or less than 25 amino acids;

(iii) peptide comprising the SEO ID NO: 3 sequence or a functionally equivalent variant, where the length of said peptide is equal or less than 25 amino acids and where the arginine and glutamine of SEQ ID NO: 3 remain unchanged;

SEQ ID NO: 1 remains unchanged;

(ii) peptide comprising the sequence SEQ ID NO: 2 or a functionally equivalent variant, wherein the length of said peptide is equal to or less than 25 amino acids; (iii) peptide comprising the sequence SEQ ID NO: 3 or a functionally equivalent variant, where the length of said peptide is equal to or less than 25 amino acids and where the arginine and glutamine of SEQ ID NO: 3 remain unchanged;

(x) peptide comprising the sequence SEQ ID NO: 12 or a functionally equivalent variant, wherein the length of said peptide is equal to or less than 20 amino acids; its stereoisomers, mixtures thereof and / or their cosmetically or pharmaceutically acceptable salts, in the manufacture of a cosmetic or pharmaceutical composition for the treatment and / or care of the skin, mucous membranes and / or nails.

(i) peptide comprising the sequence SEQ ID NO: 5 or a functionally equivalent variant, where the length of said peptide is equal to or less than 20 amino acids, and where the peptide is not the sequence peptide SEQ ID NO: 6;

Thus, in another aspect, the invention relates to a peptide selected from the group consisting of:

(iii) peptide comprising the sequence SEQ ID NO: 3 or a functionally equivalent variant, wherein the length of said peptide is equal to or less than 25 amino acids, the arginine and glutamine of SEQ ID NO: 3 is they remain unchanged and where the peptide is not the sequence peptide SEQ ID NO: 4;

SEQ ID NO: 6;

SEQ ID NO: 13;

their stereoisomers, mixtures thereof and / or their cosmetically or pharmaceutically acceptable salts, for use in medicine. In another aspect, the invention relates to a peptide selected from the group consisting of:

SEQ ID NO: 1 remains unchanged;

(viii) peptide comprising the sequence SEQ ID NO: 10 or a functionally equivalent variant, where the length of said peptide is equal to or less than 20 amino acids, and where the amino acid of the V-terminal / end of SEQ ID NO: 10 it can only be isoleucine or leucine, and the valine of said sequence remains unchanged; (ix) peptide comprising the sequence SEQ ID NO: 1 1 or a functionally equivalent variant, where the length of said peptide is equal to or less than 20 amino acids, and where the histidine of SEQ ID NO: 1 1 remains unchanged;

its stereoisomers, mixtures thereof and / or their cosmetically or pharmaceutically acceptable salts, for use in the treatment and / or prevention of pain, inflammation, pruritus, diseases and / or disorders of the respiratory tract and / or diseases and / or disorders associated with calcium imbalances.

In another aspect, the invention relates to a peptide selected from the group consisting of:

its stereoisomers, mixtures thereof and / or their cosmetically or pharmaceutically acceptable salts, for use in the treatment and / or care of the skin, mucous membranes and / or nails.

its stereoisomers, mixtures thereof and / or their cosmetically or pharmaceutically acceptable salts, for use in the inhibition of the TRPV1 receptor.

its stereoisomers, mixtures thereof and / or their cosmetically or pharmaceutically acceptable salts, for use in the inhibition of the TRPM8 receptor.

its stereoisomers, mixtures thereof and / or their cosmetically or pharmaceutically acceptable salts, for use in the inhibition of the TRPA1 receptor.

In another aspect, the invention relates to at least one peptide selected from the group consisting of:

its stereoisomers, mixtures thereof and / or their pharmaceutically acceptable salts, for use in the treatment of cancer.

Alternatively, in another aspect, the invention relates to a method of inhibiting the TRPV1 receptor comprising the administration of a cosmetic or pharmaceutically effective amount of at least one peptide, selected from the group consisting of:

(i) peptide comprising the sequence SEQ ID NO: 1 or a functionally equivalent variant, wherein the length of said peptide is equal or less than 25 amino acids and where the asparagine of the sequence SEQ ID NO: 1 remains unchanged;

In another aspect, the invention relates to a method of inhibiting the TRPM8 receptor comprising the administration of a cosmetic or pharmaceutically effective amount of at least one peptide, selected from the group consisting of:

(iii) peptide comprising the sequence SEQ ID NO: 8 or a functionally equivalent variant, where the length of said peptide is equal to or less than 20 amino acids, and where the valine and / or tryptophan of the

SEQ ID NO: 8 remain unchanged;

In another aspect, the invention relates to a method of inhibiting the TRPA1 receptor comprising the administration of a cosmetic or pharmaceutically effective amount of at least one peptide, selected from the group consisting of: (i) peptide comprising the sequence SEQ ID NO: 9 or a functionally equivalent variant, where the length of said peptide is equal to or less than 20 amino acids, and where the isoleucine of SEQ ID NO: 9 remains unchanged;

(ii) peptide comprising the sequence SEQ ID NO: 10 or a functionally equivalent variant, where the length of said peptide is equal to or less than 20 amino acids, and where the amino acid of the V-terminal / end of SEQ ID NO: 10 it can only be isoleucine or leucine, and the valine of said sequence remains unchanged;

(iii) peptide comprising the sequence SEQ ID NO: 1 1 or a functionally equivalent variant, where the length of said peptide is equal to or less than 20 amino acids, and where the histidine of SEQ ID NO: 1 1 remains unchanged;

In another aspect, the invention relates to a method for the treatment and / or prevention of pain, inflammation, pruritus, diseases and / or disorders of the respiratory tract and / or diseases and / or disorders associated with calcium imbalances comprising the administration of a cosmetically or pharmaceutically effective amount of at least one peptide, selected from the group consisting of:

their stereoisomers, mixtures thereof and / or their cosmetically or pharmaceutically acceptable salts. In another aspect, the invention relates to a method for the treatment and / or care of skin, mucous membranes and / or nails comprising the administration of a cosmetic or pharmaceutically effective amount of at least one peptide, selected from the group consisting of:

(vi) peptide comprising the sequence SEQ ID NO: 8 or a functionally equivalent variant, where the length of said peptide is equal to or less than 20 amino acids, and where the valine and / or tryptophan of the

SEQ ID NO: 8 remain unchanged;

(viii) peptide comprising the sequence SEQ ID NO: 10 or a functionally equivalent variant, where the length of said peptide is equal to or less than 20 amino acids, and where the amino acid of the / V-terminal end of SEQ ID NO: 10 can only be isoleucine or leucine, and the valine of said sequence remains unchanged;

In another aspect, the invention relates to a method of cancer treatment, which comprises the administration of a therapeutically effective amount of at least one peptide selected from the group consisting of:

their stereoisomers, mixtures thereof and / or their pharmaceutically acceptable salts.

In a particular embodiment, the cancer is prostate cancer and / or pancreatic cancer.

In a particular embodiment, the amino-terminal (/ V-terminal) and carboxy-terminal (C-terminal) ends of the above peptide sequences may be chemically modified. According to a preferred embodiment, the / V-terminal substituent is selected from the group consisting of H, a polymer derived from polyethylene glycol and R-CO-, where R is selected from the group consisting of C1-C24 alkyl radical substituted or not substituted, substituted or unsubstituted C ₂ -C ₂ 4 alkenyl, substituted or unsubstituted C ₂ -C 24 alkynyl, substituted or unsubstituted C 3 -C 24 cycloalkyl, substituted or unsubstituted C ₅ -C ₂₄ cycloalkenyl, substituted C ₈ -C ₂ 4 cycloalkenyl or unsubstituted, C ₆ -C ₃ or substituted or unsubstituted aryl, substituted or unsubstituted C ₇ -C 24 aralkyl, substituted or unsubstituted 3-10 ring heterocyclyl, and substituted or unsubstituted heteroarylalkyl of 2 to 24 carbon atoms and 1 to 3 atoms other than carbon and an alkyl chain of 1 to 6 carbon atoms and R-CO- is not an α-amino acid. More preferably, the end / V-terminal substituent is selected from the group consisting of H, a polymer derived from polyethylene glycol of molecular weight between 200 and 35,000 Daltons, acetyl, irec-butanoyl, prenyl, hexanoyl, 2-methylhexanoyl, cyclohexanecarboxyl, octanoyl, decanoyl, lauroyl, myristoyl, palmitoyl, stearoyl, oleoyl and linoleoyl. Even more preferably, the / V-terminal substituent is H, acetyl, lauroyl, myristoyl or palmitoyl. In an even more preferred embodiment, R1 is acetyl or palmitoyl.

According to another preferred embodiment, the C-terminal substituent is selected from the group consisting of -NR ^, -OR1, -SR1, where R1 and R ₂ are independently selected from the group consisting of H, a polymer derived from polyethylene glycol, C1-C24 substituted or unsubstituted alkyl, alkenyl C ₂ -C _{4 February} substituted or unsubstituted alkynyl , C ₂ -C _{4 February} substituted or unsubstituted, C3-C24 substituted or unsubstituted cycloalkyl , C5-C24 substituted or unsubstituted , substituted or unsubstituted C ₈ -C ₂ 4 cycloalkynyl, C ₆ -C ₃ or substituted or unsubstituted aryl, substituted or unsubstituted C ₇ -C 24 aralkyl, substituted or unsubstituted 3-10 ring heterocyclyl, and substituted heteroarylalkyl or unsubstituted from 2 to 24 carbon atoms and 1 to 3 atoms other than carbon where the alkyl chain is 1 to 6 carbon atoms and -NR- | R ₂ is not an α-amino acid. Optionally, R1 and _R2 may be joined by a carbon-carbon, saturated or unsaturated, forming a cycle with the nitrogen atom bond. More preferably the substituent of the C-terminal end is -NR- | R ₂ or -OR1. More preferably, R 1 and R ₂ are selected from the group consisting of H, a polymer derived from polyethylene glycol of molecular weight between 200 and 35,000 Daltons, methyl, ethyl, hexyl, dodecyl and hexadecyl. Even more preferably R1 is H and R ₂ is selected from the group consisting of H, methyl, ethyl, hexyl, dodecyl and hexadecyl According to an even more preferred embodiment, the C-terminal substituent is selected from -OH and -NH ₂ .

In another particular embodiment, the peptides of the invention or their functionally equivalent variants, their stereoisomers, mixtures thereof and / or their cosmetically or pharmaceutically acceptable salts, are used for the treatment and / or prevention of pain, inflammation and / or pruritus. that are a consequence or concur with epithelial, gastrointestinal diseases or disorders of the cardiovascular system, urinary tract, endocrine system, brain, reproductive system, respiratory tract and / or cancer.

In another particular embodiment, the pain is selected, for example and without limitation, from the group consisting of acute pain, chronic pain, nociceptive pain, neuropathic pain, inflammatory pain, visceral pain, abdominal pain, digestive system pain, system pain respiratory, urogenital system pain, endocrine system pain, heart pain, pancreatic pain, liver pain, pain due to gallstones, cholestasis, intestinal pain, stomach pain, pain due to duodenal ulcer, pain due to esophagitis, pain due at gastroesophageal reflux, spleen pain, blood vessel pain, pain due to thalamic syndrome, irritable bowel syndrome, pain associated with Crohn's disease, diverticulitis, gastrointestinal mucositis, headache, tension headache, headache associated with sinusitis, migraine, eye pain, dry eye syndrome, post-operative pain, post-operative pain due to incisions s surgery, post-operative pain due to the insertion of bone implants, post-operative pain due to bone replacement, post-operative pain due to infections, post-operative pain due to limb amputations, pain due to bone fractures, pain due to cancer, pain due to bone cancer, pain associated with benign bone tumors, pain associated with osteoid osteomas, pain associated with osteoblastomas, pain due to cancer treatment, pain due to chemotherapy, pain due to emesis pain due to emesis resulting from chemotherapy treatment, musculoskeletal pain, spastic muscle pain, fibromyalgia, complex regional pain syndrome, psychogenic pain, nerve pain, pain due to demyelinating diseases, neck pain associated with cervical dystonia, back pain , low back pain, sciatica, neurogenic inflammation, neuritis, causalgia, sensitivity to touch, sensitivity to cold, s heat sensitivity, skin irritation, postdepilation skin irritation, post-shave skin irritation, psoriasis, sensitive skin, dermatitis, atopic dermatitis, contact dermatitis, diaper dermatitis, eczema, burns, sunburn, arthritis, rheumatoid arthritis, osteoarthritis, psoriatic arthritis, uveitis, pain due to nerve injuries, neuralgia, post-herpetic neuralgia, neuropathies, peripheral neuropathies, phantom pain, allodynia, hyperalgesia, cold hyperalgesia, pain due to tunnel syndrome carpal, burning pain, Grierson-Gopalan syndrome (better known as burning foot syndrome), burning mouth syndrome, paraesthesia, Fabry disease, facial pain, trigeminal neuralgia, neuropathic pain due to diabetes, neuropathic pain due AIDS, orofacial pain, dental pain, tooth extraction pain, wisdom tooth extraction pain, cold dental sensitivity, heat dental sensitivity, oral mucositis, temporomandibular joint pain, associated pain from tattoo processes or tattoo removal, pain due to bunions, testicular pain, myofascial pain, urinary bladder pain, traumatic pain urinary tract, cystitis, pain due to kidney stones, renal colic, vulvar pain, vaginal pain, postpartum pain, menstrual pain, scrotal pain, perineal pain, pelvic pain or hypersensitivity, skin pain or irritation after surgery, after surgery treatment with pulsed light therapy (IPL, Intense Pulse Light), after treatment with monochromatic pulsed light therapy (laser), after treatment with chemical descaling agents or after overexposure to aggressive external agents and pain due to chronic alcoholism. In a preferred embodiment, the pain is neuropathic pain and / or inflammatory pain.

In another particular embodiment, the inflammation is selected, for example and without limitation, from the group consisting of neurogenic inflammation, joint inflammation, tendon inflammation, muscle inflammation, sepsis, vascular inflammation, respiratory inflammation, chronic obstructive pulmonary disease, asthma, otitis, intestinal inflammation, pancreatitis, hepatitis, conditions related to chronic inflammation, with acute inflammation, nephritis, systemic lupus erythematosus, inflammatory bowel disease, Crohn's disease, rheumatoid arthritis, osteoarthritis, glomerulonephritis, neuritis, nervous tissue inflammation, multiple sclerosis, immune system disorders, Sjógren's syndrome, rhinitis, atherosclerosis, myocarditis, pericarditis, vasculitis, psoriasis, sensitive skin, dermatitis, atopic dermatitis, contact dermatitis, diaper dermatitis, eczema, rosacea, burns, sunburn, vulvodynia, diseases inflammatory eyes, and sarcoidosis, among others.

In another particular embodiment, the pruritus is selected from the itching associated with diseases and / or epithelial disorders, such as and without limitation, dermatitis, atopic dermatitis, photodermatosis, eczema, sensitive skin, psoriasis, dandruff, seborrhea, athlete's foot, sunburn, xerosis and dry skin, or pruritus associated with dialysis, pregnancy, menopause, acquired immunodeficiency virus infection, chicken pox, herpes, malignant neoplasms, Hodgkin's disease, leukemia, myeloma , lymphoma, solid tumors, lung cancer, liver diseases, jaundice, cholestasis, liver failure, cirrhosis, polycythemia, hypereosinophilic syndrome, essential thrombocythemia, myelodysplastic syndrome, iron deficiency anemia, systemic lupus erythematosus, endocrine diseases, thyroid diseases, parathyroid diseases, diabetes mellitus, kidney diseases, uremia, parasitic infections, scabies, lice, intestinal worms, allergic reactions, drug allergies, food allergies, chemical allergies, exposure to poisonous plants, exposure to insect bites, chemotherapy, stress and anxiety, among others.

In another particular embodiment, respiratory diseases and / or disorders are selected, for example and without limitation, from the group consisting of obstructive diseases such as chronic obstructive pulmonary disease, emphysema, chronic bronchitis, asthma, asthma caused by industrial irritants, cystic fibrosis, bronchiectasis, bronchiolitis, allergic bronchopulmonary aspergillosis, or tuberculosis; Restrictive pulmonary diseases such as asbestosis, radiation-caused fibrosis, extrinsic allergic alveolitis or insensitivity pneumonitis, childhood respiratory distress syndrome, idiopathic pulmonary fibrosis, sarcoidosis, idiopathic interstitial pneumonia, eosinophilic pneumonia, lymphangioleiomyomatosis, Langerhave alveolar and pulmonary cell histiocytosis pulmonary; respiratory tract infections including common cold, sinusitis, tonsillitis, pharyngitis, laryngitis or pneumonia; Respiratory malignant tumors such as small cell lung cancer, non-small cell lung cancer, adenocarcinoma, squamous cell carcinoma, undifferentiated large cell carcinoma, carcinoid, mesothelioma, metastatic lung cancer, germ cell metastatic cancer, benign respiratory tumors as pulmonary hamartoma; congenital malformations such as bronchopulmonary sequestration and cystic adenomatoid congenital malformation; diseases of the pleural cavity such as empyema and mesothelioma; pulmonary vascular diseases such as embolism, pulmonary thromboembolism, gas embolism (iatrogenic), pulmonary arterial hypertension, pulmonary edema, pulmonary hemorrhage, inflammation and damage to the capillaries in the lungs resulting in blood dripping into the alveoli; disorders that affect the mechanics of breathing such as obstructive sleep apnea, central apnea of sleep, amyotrophic lateral sclerosis, Guillain-Barré syndrome and myasthenia gravis; shortness of breath or breathlessness, cough (with or without sputum production), coughing up blood (hemoptysis), chest pain such as pleuritic chest pain, noisy breathing, wheezing and cyanosis, among others.

In another particular embodiment, the diseases and / or disorders associated with calcium imbalances are selected, for example and without limitation, from the group consisting of vitamin D deficiency, rickets, osteomalacia, growth retardation, osteoporosis, post-menopausal osteoporosis , hypercalciuria, hypocalciuria, hypercalcemia, hypocalcemia and disorders related to parathyroid hormone, among others.

In another particular embodiment, gastrointestinal diseases and / or disorders are selected, for example and without limitation, from the group consisting of inflammatory bowel disease, intestinal colic, Crohn's disease, pancreatitis, hepatitis, gastroesophageal reflux disease, duodenal ulcer, esophagitis , colitis or ulcerative colitis, among others.

In another particular embodiment, epithelial diseases and / or disorders are selected, for example and without limitation, from the group formed by touch sensitivity, cold sensitivity, heat sensitivity, skin irritation, post-depilation skin irritation, post skin irritation -have, dermatitis, atopic dermatitis, allergic contact dermatitis, diaper dermatitis, photodermatosis, psoriasis, eczema, rosacea, burns, sunburn, sensitive skin, xerosis or dry skin among others.

In another particular embodiment, cardiovascular diseases and / or disorders are selected, for example and without limitation, from the group consisting of angina, ischemia, reperfusion, hypertension, chronic heart disease or cardiac fibrosis, among others.

In another particular embodiment, brain diseases and / or disorders are selected, for example and without limitation, from the group consisting of cerebral infarction, cerebral ischemia, cognitive disorders, memory problems, schizophrenia, bipolar disorder, Alzheimer's disease (AD) , Parkinson's disease, Huntington's disease, neurodegeneration, stroke, post stroke pain, multiple sclerosis, amyotrophic lateral sclerosis (ALS), and other brain disorders caused by trauma or other insults including aging, among others. In another particular embodiment, diseases and / or disorders of the urinary tract are selected, for example and without limitation, from the group formed by urinary incontinence, overactive bladder syndrome, cystitis, urination disorders, pain associated with kidney stones and renal colic, among others.

In another particular embodiment, diseases and / or disorders of the reproductive system are selected, for example and without limitation, from the group formed by vulvodynia, menstrual pain and vaginitis, among others.

In another particular embodiment, the diseases and / or disorders associated with different types of cancer and / or their treatment are selected, for example and without limitation, from the group consisting of neoplasms of lymphoreticular origin, bone cancer, osteosarcoma, liposarcoma, cancer breast, neoplasms of lymphoreticular origin, bladder cancer, colon cancer, endometrial cancer, head and neck cancer, lung cancer, melanoma, ovarian cancer, prostate cancer, skin cancer and rectal cancer, among others .

EXAMPLES

The following examples serve to illustrate the invention and should not be considered as limiting the scope thereof.

Abbreviations

The abbreviations used for amino acids follow the 1983 recommendations of the Biochemical Nomenclature Commission of the IUPAC-IUB specified in Eur. J. Biochem. (1984) 138: 9-37.

®, resin; Ac, acetyl; Adpoc, 1 - (1 -adamantil) -1-methylethoxycarbonyl; There, alilo; Alloc, allyloxycarbonyl; AM, 2- [4-aminomethyl- (2,4-dimethoxyphenyl)] -phenoxyacetic acid; Boc, íerc-butyloxycarbonyl; Bom, benzyloxymethyl; 2-BrZ, 2-bromobenzyloxycarbonyl; Bzl, benzyl; α-CGRP, peptide related to the α-calcitonin gene; cHx, cyclohexyl; 2-CITrt-®, 2-chlorotritylresin; CIZ, 2-chlorobenzyl; C-terminal, carboxy-terminal; DCM, dichloromethane; Dde, / V- [1 - (4,4-dimethyl-2,6-dioxcyclohex-1-ylidene) ethyl; 2,6-diCIZ, 2,6-dichlorobenzyloxycarbonyl; DIEA, Λ /, / V-diisopropylethylamine; DIPCDI, Λ /, Λ / '- diisopropylcarbodiimide; Dmab, 4 - (/ V- [1 - (4,4-dimethyl-2,6-dioxcyclohexylidene) -3-methylbutyl] amino) benzyl; DMEM, half Eagle modified by Dulbecco; DMF, Λ /, / V-dimethylformamide; DMSO, dimethylsulfoxide; Dnp, 2,4-dinitrophenyl; DRG, dorsal root ganglion; eq., equivalent; ES-MS, electrospray mass spectrometry; FBS, fetal bovine serum; FCS, fetal calf serum; Fm, fluorenylmethyl; Fmoc, fluorenylmethoxycarbonyl; For, formyl; HBBS, Hank buffered saline; HEPES, 4- (2-hydroxyethyl) piperazine-1-ethanesulfonic acid; HOBt, 1-hydroxybenzotriazole; HPLC, high performance liquid chromatography; ivDde, 1 - (4,4-dimethyl-2,6-dioxo-cyclohexylidene) -3-methyl-butyl; MBHA, p-methylbenzhydrylamine resin; Me, methyl; MeCN, acetonitrile; MEM, Earle's essential minimum medium; MeOH, methanol; MES, 2- (/ V-morpholino) ethanesulfonic acid; Mtr, 4-methoxy-2,3,6-trimethylbenzenesulfonyl; Mts, mesitylene-2-sulfonyl; Mtt, methoxytrityl; 4-nitroZ or pNZ, para-nitrobenzyloxycarbonyl; NMP, / V-methylpyrrolidone; / V-terminal, amino-terminal; Palm, palmitoyl; Pbf, 2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl; Pmc, 2,2,5,7,8-pentamethylchroman-6- sulfonyl; rpm, revolutions per minute; tBu, íerc-butyl; Teoc, 2- (trimethylsilyl) ethyloxycarbonyl; TFA, trifluoroacetic acid; THF, tetrahydrofuran; TIS, triisopropylsilane; TMS, trimethylsilylethyl; Cough, tosyl; Trt, trityl or triphenylmethyl; Troc, 2,2,2-trichlorethyloxycarbonyl; Xan, β-xantyl; Z, benzyloxycarbonyl.

General Methodology: Chemical Synthesis

All synthetic processes were carried out in polypropylene syringes equipped with porous polyethylene discs. All reagents and solvents were of quality for synthesis and were used without any additional treatment. Solvents and soluble reagents were removed by suction. The removal of the Fmoc group was carried out with piperidine-DMF (2: 8, v / v) (1 x 1 min, 1 x 5 min; 5 mL / g resin) [Lloyd-Williams P., Albericio F. and Giralt, E. (1997) "Chemical Approaches to the Synthesis of Peptides and Proteins" CRC, Boca Raton (FL, USA)]. The washings between the steps of deprotection, coupling, and, again, deprotection were carried out with DMF (3 x 1 min) each time using 10 mL solvent / g resin. Coupling reactions were performed with 3 mL solvent / g resin. Coupling control was performed by ninhydrin assay [Kaiser E.eí al. (1970) Anal. Biochem 34: 595-598] or chloranil [Christensen T. (1979) Acta Chem. Scand. 33B: 763-766]. All synthetic transformations and washes were carried out at 25 ° C.

Electrospray mass spectrometry analysis was carried out in a WATERS Alliance with a ZQ 2000 detector using a mixture of MeCN: H ₂ 0 4: 1 (+ 0.1% TFA) as mobile phase and a flow of 0 , 2 mL / min. EXAMPLE 1

Fmoc-L-Ala-AM-MBHA,

Fmoc-L-Ara (Pbf) -AM-MBHA, Fmoc-L-Asn (Trt) -AM-MBHA,

Fmoc-L-Glu (OtBu) -AM-MBHA, Fmoc-L-L vs (Boc) -AM-MBHA,

Fmoc-L-Ser (tBu) -AM-MBHA, Fmoc-L-Val-AM-MBHA, Fmoc-Glv-O-2-CITrt-®,

Fmoc-L-Ala-O-2-CITrt-®, Fmoc-L-Am (Pbf) -0-2-CITrt-®, Fmoc-L-Asn (Trt) -0-2-CITrt-®,

Fmoc-L-Glu (OtBu) -0-2-CITrt-®, Fmoc-L-Lvs (Boc) -0-2-CITrt-®,

Fmoc-L-Ser (tBu) -0-2-CITrt-® v Fmoc-L-Val-O-2-CITrt-®.

10.0 g of the 0.64 mmol / g functionalization Fmoc-AM-MBHA resin was treated with piperidine-DMF according to the general protocol described in order to eliminate the Fmoc group. After the DMF washes after the deprotection step, the unprotected resin was divided into 8 equal aliquots on which 0.59 g of Fmoc-Gly-OH, 0.66 g of Fmoc-L-Ala-OH were incorporated, 1.30 g of Fmoc-L-Arg (Pbf) -OH, 1.19 g of Fmoc-L-Asn (Trt) -OH, 0.89 g of Fmoc-L-Glu (OtBu) -OH, 0, 94 g of Fmoc-L-Lys (Boc) -OH, 0.77 g of Fmoc-L-Ser (tBu) -OH or 0.68 g of Fmoc-L-Val-OH (2.0 mmol) in the presence of DIPCDI (0.31 ml_; 2.0 mmol) and HOBt (0.31 g; 2.0 mmol) using DMF as solvent for 1 h.

Alternatively, 0.24 g of Fmoc-Gly-OH, 0.26 g of Fmoc-L-Ala- were incorporated onto 0.50 g of functionalization 2-chlorotrityl resin 1.60 mmol / g (0.8 mmol). OH, 0.52 g of Fmoc-L-Arg (Pbf) -OH, 0.48 g of Fmoc-L-Asn (Trt) -OH, 0.35 g of Fmoc-L-Glu (OtBu) -OH, 0.37 g of Fmoc-L-Lys (Boc) -OH, 0.31 g of Fmoc-L-Ser (tBu) -OH or 0.27 g of Fmoc-L-Val-OH (0.8 mmol) dissolved in 5 ml_ of DCM to which 0.12 ml_ of DIEA (0.69 mmol) was added. They were allowed to stir for 5 min, after which 0.23 mL of DIEA (1.33 mmol) was added. They were allowed to react for 40 min after which the remaining chloride groups were blocked by treatment with 0.4 mL of MeOH.

After the incorporation time of the amino acids, the aminoacyl resins obtained were washed with DMF (5 x 1 min), DCM (4 x 1 min), diethyl ether (4 x 1 min) and dried in vacuo.

EXAMPLE 2 Obtaining Fmoc-L-Met-Glv-L-Glu (OtBu) -L-Thr (tBu) -L-Val-L-Asn (Trt) -AM-MBHA and Fmoc-L-Me G / ^ / - ■ ■ -G / ί / Ofeί /) ---- 7 / ^^ eί /) ---- \ a / - ■■ - / sn 7f) -0-2-C / 7f -®

0.2 mmol (1 eq.) Of the aminoacyl-resins Fmoc-L-Asn (Trt) -AM-MBHA and Fmoc-L-Asn (Trt) -0-2-CITrt-® were washed and unprotected as described in general methods to incorporate the following amino acids. On each of the two resins and following the described protocols, 0.17 g of Fmoc-L-Val-OH, 0.20 g of Fmoc-L-Thr (tBu) -OH, 0.22 g of Fmoc-L-Glu (OtBu) -OH, 0.15 g of Fmoc-Gly-OH and 0.19 g of Fmoc-L-Met-OH (0.5 mmol; 2.5 eq.) In the presence of each coupling 76.5 mg of HOBt (0.5 mmol; 2.5 eq.) and 77.3 μΙ_ of DIPCDI (0.5 mmol; 2.5 eq.).

After the synthesis, the peptidyl resins obtained were washed with DMF (5 x 1 min), DCM (4 x 1 min), diethyl ether (4 x 1 min) and dried in vacuo.

EXAMPLE 3

Obtaining of

Fmoc-L- ¾sn 7f -¿.-¿. s eoc -¿ .- // e-¿.- / /a-¿.-G/n 7f -¿.-G / Í / OfeÍ / ---- Se eÍ / -

-AM-MBHA y_

Fmoc-L- ¾sn 7f -L-L s eoc -L - // e-L- ¾ / a-L-G / n 7f -¿.-G / Í / Ofeü ---- Be eÍ / -

-Ο-2-CITrt-®

0.2 mmol (1 eq.) Of the amino-acyl resins Fmoc-L-Ser (tBu) -AM-MBHA and

Fmoc-L-Ser (tBu) -0-2-CITrt-® was washed and deprotected as described in the general methods for incorporating the following amino acids. On each of the two resins and following the described protocols, 0.22 g of Fmoc-L-Glu (OtBu) -OH, 0.31 g of Fmoc-L-Gln (Trt) -OH, 0, were sequentially coupled. 16 g of Fmoc-L-Ala-OH, 0.18 g of Fmoc-L-lle-OH, 0.23 g of Fmoc-L-Lys (Boc) -OH and 0.30 g of Fmoc-L-Asn (Trt) -OH (0.5 mmol; 2.5 eq.) In the presence at each coupling of 76.5 mg of HOBt (0.5 mmol; 2.5 eq.) And 77.3 μΙ_ of DIPCDI (0 , 5 mmol; 2.5 eq.).

EXAMPLE 4 Obtaining Fmoc-L-Met-Glv-L-Glu (OtBu) -L-Thr (tBu) -L-Val-L-Asn (Trt) -L-Lvs (Boc) -

-L-lle-L-Ala-L-Gln (Trt) -L-Glu (OtBu) -L-Ser (tBu) -AM-MBHA y_

Fmoc-L-Met-Glv-L-Glu (OtBu) -

-L-T r (tBu) -L-Val-L-Asn (Trt) -L-Lvs (Boc) -L-lle-L-Ala-L-Gln (

0-2- -CITrt-®

0.2 mmol (1 eq.) Of the aminoacyl-resins Fmoc-L-Ser (tBu) -AM-MBHA and Fmoc-L-Ser (tBu) -0-2-CITrt-® were washed and unprotected as described in general methods to incorporate the following amino acids. On each of the two resins and following the described protocols, 0.22 g of Fmoc-L-Glu (OtBu) -OH, 0.31 g of Fmoc-L-Gln (Trt) -OH, 0, were sequentially coupled. 16 g of Fmoc-L-Ala-OH, 0.18 g of Fmoc-L-lle-OH, 0.23 g of Fmoc-L-Lys (Boc) -OH, 0.30 g of Fmoc-L-Asn (Trt) -OH, 0.17 g of Fmoc-L-Val-OH, 0.20 g of Fmoc-L-Thr (tBu) -OH, 0.22 g of Fmoc-L-Glu (OtBu) -OH , 0.15 g of Fmoc-Gly-OH and 0.19 g of Fmoc-L-Met-OH (0.5 mmol; 2.5 eq.) In the presence in each coupling of 76.5 mg of HOBt (0 , 5 mmol; 2.5 eq.) And 77.3 μΙ_ of DIPCDI (0.5 mmol; 2.5 eq.).

EXAMPLE 5

Obtaining of

Fmoc-L-lle-L-TrD (Boc) -L-Lvs (Boc) -L-Leu-L-Gln (m-L-ArQ (Pbf) -AM-MB y_

Fmoc-L - // e-L-7rp eoc -L-L s eoc -L-Leü-¿.-G / n 7rf -¿ .- / ra Pibfí-0-2-C / 7f -®

0.2 mmol (1 eq.) Of the aminoacyl-resins Fmoc-L-Arg (Pbf) -AM-MBHA and Fmoc-L-Arg (Pbf) -0-2-CITrt-® were washed and unprotected as described in general methods to incorporate the following amino acids. On each of the two resins and following the described protocols, 0.31 g of Fmoc-L-Gln (Trt) -OH, 0.18 g of Fmoc-L-Leu-OH, 0.23 g of Fmoc-L-Lys (Boc) -OH, 0.26 g of Fmoc-L-Trp (Boc) -OH and 0.18 g of Fmoc-L-lle-OH (0.5 mmol; 2.5 eq. ) in the presence of 76.5 mg of HOBt (0.5 mmol; 2.5 eq.) and 77.3 μ 77_ of DIPCDI (0.5 mmol; 2.5 eq.) in each coupling.

After the synthesis, the peptidyl resins obtained were washed with DMF (5 x 1 min), DCM (4 x 1 min), diethyl ether (4 x 1 min) and dried in vacuo. EXAMPLE 6

Obtaining of

Fmoc-L-Me G / ^ / - LG / ü Ofeü) ---- 7 / ^^ eü) -L- \ a / -L- ¾sn 7f) -LL ^ / s eoc) - ■■ - // e- -L-Ala-L-Gln (Trt) -L-Glu (OtBu) -AM-MBHA and Fmoc-L-Met-Glv-L-Glu (OtBu) -L-Thr (tBu) - -L- \ a / -L- ¾sn 7f) -LL s eoc) -L - // eL- ¾ / aLG / n 7f) -LG / ü Ofeü) -0-2-C / 7f -®

0.2 mmol (1 eq.) Of the aminoacyl-resins Fmoc-L-Glu (OtBu) -AM-MBHA and Fmoc-L-Glu (OtBu) -0-2-CITrt-® were washed and unprotected as described in general methods to incorporate the following amino acids. On each of the two resins and following the described protocols, 0.31 g of Fmoc-L-Gln (Trt) -OH, 0.16 g of Fmoc-L-Ala-OH, 0.18 g of Fmoc-L-lle-OH, 0.23 g of Fmoc-L-Lys (Boc) -OH, 0.20 g of Fmoc-L-Asn (Trt) -OH, 0.17 g of Fmoc-L-Val -OH, 0.20 g of Fmoc-L-Thr (tBu) -OH, 0.22 g of Fmoc-L-Glu (OtBu) -OH, 0.15 g of Fmoc-Gly-OH and 0.19 g of Fmoc-L-Met-OH (0.5 mmol; 2.5 eq.) in the presence at each coupling of 76.5 mg of HOBt (0.5 mmol; 2.5 eq.) and 77.3 μΙ_ of DIPCDI (0.5 mmol; 2.5 eq.).

EXAMPLE 7

Obtaining of

Fmoc-L-Met-Giv-L-Giu (OtBu) -L-Thr (tBu) -L-Vai-L-Asn (-L-Lvs (Boc) -U ^^

-L-Ala-L-Gln (Trt) -L-Glu (OtBu) -L-Ser (tBu) -L-Lvs (Boc) -L-Asnq

Boc) -L-Leu-L-Gln (Trt) -L-Arg (Pbf) -L-Ala-AM-MBHA and Fmoc-L-Met-Glv-L-Glu (OtBu) - -L-Thr (tBu ) -L-Val-L-Asn (mL-Lvs (Boc) -L-lle-L-Ala-L-Gln (T ^

-L-Lvs (Boc) -L-Asn (Trt) -L-lle-L-TrD (Boc) -L-Lvs (Boc) -L-Leu-L-Glnm ^

O- -2-CITrt-®

0.2 mmol (1 eq.) Of the aminoacyl-resins Fmoc-L-Ala-AM-MBHA and Fmoc-L-Ala-O-2-CITrt-® were washed and deprotected as described in the general methods for incorporating The following amino acids. On each of the two resins and following the described protocols, 0.32 g of Fmoc-L-Arg (Pbf) -OH, 0.31 g of Fmoc-L-Gln (Trt) -OH, 0, were sequentially coupled. 18 g of Fmoc-L-Leu-OH, 0.23 g of Fmoc-L-Lys (Boc) -OH, 0.26 g of Fmoc-L-Trp (Boc) -OH, 0.18 g of Fmoc- L-lle-OH, 0.30 g of Fmoc-L-Asn (Trt) -OH, 0.23 g of Fmoc-L-Lys (Boc) -OH, 0.19 g of Fmoc-L-Ser (tBu) -OH, 0.22 g of Fmoc-L-Glu (OtBu) -OH, 0.31 g of Fmoc-L-Gln (Trt) -OH, 0.16 g of Fmoc -L-Ala-OH, 0.18 g of Fmoc-L-lle-OH, 0.23 g of Fmoc-L-Lys (Boc) -OH, 0.30 g of Fmoc-L-Asn (Trt) - OH, 0.17 g of Fmoc-L-Val-OH, 0.20 g of Fmoc-L-Thr (tBu) -OH, 0.22 g of Fmoc-L-Glu (OtBu) -OH, 0.15 g of Fmoc-Gly-OH and 0.19 g of Fmoc-L-Met-OH (0.5 mmol; 2.5 eq.) in the presence at each coupling of 76.5 mg of HOBt (0.5 mmol; 2.5 eq.) And 77.3 μΙ_ of DIPCDI (0.5 mmol; 2.5 eq.).

EXAMPLE 8

Obtaining Fmoc-L-Phe-Glv-L-Tyr (tBu) -L-Thr (tBu) -L-Val-Glv-AM-MBHA and Fmoc-L-Phe-Glv-L-Tyr (tBu) -L -Thr (tBu) -L-Val-Glv-Q-2-CITrt-®

0.2 mmol (1 eq.) Of the amino-acyl resins Fmoc-Gly-AM-MBHA and Fmoc-Gly-O-2-CITrt-® were washed and deprotected as described in the general methods for incorporating the following amino acids. On each of the two resins and following the described protocols, 0.17 g of Fmoc-L-Val-OH, 0.20 g of Fmoc-L-Thr (tBu) -OH, 0.23 g of were sequentially coupled Fmoc-L-Tyr (tBu) -OH, 0.15 g of Fmoc-Gly-OH and 0.19 g of Fmoc-L-Phe-OH (0.5 mmol; 2.5 eq.) In the presence of each coupling 76.5 mg of HOBt (0.5 mmol; 2.5 eq.) and 77.3 μΙ_ of DIPCDI (0.5 mmol; 2.5 eq.).

EXAMPLE 9

Obtaining Fmoc-L-Thr (tBu) -L-Val-L-Gln (Trt) -L-Glu (OtBu) -L-Asn (Trt) -L-Asn (Trt) - -AM-MBHA and Fmoc- L-7 /? R ^ eü -¿ - \ a / -¿.-G / n 7f -¿.-G / Í / OfeÍ / ---- / sn 7f -¿ .- / sn 7f - -Ο -2-CITrt-®

0.2 mmol (1 eq.) Of the aminoacyl-resins Fmoc-L-Asn (Trt) -AM-MBHA and Fmoc-L-Asn (Trt) -0-2-CITrt-® were washed and unprotected as described in general methods to incorporate the following amino acids. On each of the two resins and following the described protocols, 0.30 g were sequentially coupled of Fmoc-L-Asn (Trt) -OH, 0.22 g of Fmoc-L-Glu (OtBu) -OH, 0.31 g of Fmoc-L-Gln (Trt) -OH, 0.17 g of Fmoc -L-Val-OH and 0.20 g of Fmoc-L-Thr (tBu) -OH (0.5 mmol; 2.5 eq.) In the presence in each coupling of 76.5 mg of HOBt (0.5 mmol; 2.5 eq.) and 77.3 μΙ_ of DIPCDI (0.5 mmol; 2.5 eq.) - After the synthesis, the obtained peptidyl resins were washed with DMF (5 x

1 min), DCM (4 x 1 min), diethyl ether (4 x 1 min) and dried in vacuo.

EXAMPLE 10

Obtaining Fmoc-L-Phe-Glv-L-Tyr (tBu) -L- Thr (tBu) -L-Val-Glv-L-Thr (tBu) -L-Val- -L-Gln (Trt) -L -Glu (OtBu) -L-Asn (Trt) -L-Asn (Trt) -AM-MBHA y_

Fmoc-L-Phe-Giy-L-Tyr (tBu) -

-L-Thr (tBu) -L-Val-Glv-L-Thr (tBu) -L-Val-L-Gln (m-L-Glu (OtBu ^

2- -CITrt-®

0.2 mmol (1 eq.) Of the aminoacyl-resins Fmoc-L-Asn (Trt) -AM-MBHA and Fmoc-L-Asn (Trt) -0-2-CITrt-® were washed and unprotected as described in general methods to incorporate the following amino acids. On each of the two resins and following the described protocols, 0.30 g of Fmoc-L-Asn (Trt) -OH, 0.22 g of Fmoc-L-Glu (OtBu) -OH, 0, were sequentially coupled. 31 g of Fmoc-L-Gln (Trt) -OH, 0.17 g of Fmoc-L-Val-OH, 0.20 g of Fmoc-L-Thr (tBu) -OH, 0.15 g of Fmoc- Gly-OH, 0.17 g of Fmoc-L-Val-OH, 0.20 g of Fmoc-L-Thr (tBu) -OH, 0.23 g of Fmoc-L-Tyr (tBu) -OH, 0 , 15 g of Fmoc-Gly-OH and 0.19 g of Fmoc-L-Phe-OH (0.5 mmol; 2.5 eq.) In the presence in each coupling of 76.5 mg of HOBt (0.5 mmol; 2.5 eq.) and 77.3 μί of DIPCDI (0.5 mmol; 2.5 eq.).

EXAMPLE 11

Obtaining Fmoc-L-Asn (Trt) -L-AsD (OtBu) -L-Gin (Trt) -L-Vai-L-TrD (Boc) -L-Lys (Boc) - -AM-MBHA and Fmoc- L-Asn (Trt) -L-AsD (OtBu) -L-Gln (Trt) -L-Val-L-TrD (Boc) -L-Lvs (Boc) - -Ο-2-CITrt-®

0.2 mmol (1 eq.) Of the aminoacyl-resins Fmoc-L-Lys (Boc) -AM-MBHA and Fmoc-L-Lys (Boc) -0-2-CITrt-® were washed and unprotected as described in the general methods to incorporate the following amino acids. On each of the two resins and following the described protocols, 0.26 g of Fmoc-L-Trp (Boc) -OH, 0.17 g of Fmoc-L-Val-OH, 0.31 g of Fmoc-L-Gln (Trt) -OH, 0.21 g of Fmoc-L-Asp (OtBu) -OH and 0.30 g of Fmoc-L-Asn (Trt) -OH (0.5 mmol; 2, 5 eq.) In the presence at each coupling of 76.5 mg of HOBt (0.5 mmol; 2.5 eq.) And 77.3 μΙ_ of DIPCDI (0.5 mmol; 2.5 eq.).

EXAMPLE 12

Obtaining Fmoc-L-Phe-Glv-L-Tyr (tBu) -L- Thr (tBu) -L-Val-Glv-L-Thr (tBu) -L-Val- -L-Gln (Trt) -L -Glu (OtBu) -L-Asn (Trt) -L-Asn (Trt) -L-Asp (OtBu) -LG

- -L-Lvs (Boc) -L-Phe-L-Gln (Trt) -L-Arg (Pbf) -AM-MBHA and Fmoc-L-Phe-Gly-L-Tyr (tBu) - -L-Thr (tBu) -L-Val-Glv-L-Thr (tBu) -L-Val-L-Gln (mL-Glu (OtBu ^

-L-AsD (OtBu) -L-Gln (Trt) -L-Val-L-TrD (Boc) -L-Lvs (Boc) -L-Phe-L ^

-2-CITrt-®

0.2 mmol (1 eq.) Of the aminoacyl-resins Fmoc-L-Arg (Pbf) -AM-MBHA and Fmoc-L-Arg (Pbf) -0-2-CITrt-® were washed and unprotected as described in general methods to incorporate the following amino acids. On each of the two resins and following the described protocols, 0.31 g of Fmoc-L-Gln (Trt) -OH, 0.19 g of Fmoc-L-Phe-OH, 0.23 g of Fmoc-L-Lys (Boc) -OH, 0.26 g of Fmoc-L-Trp (Boc) -OH, 0.17 g of Fmoc-L-Val-OH, 0.31 g of Fmoc-L-Gln (Trt) -OH, 0.21 g of Fmoc-L-Asp (OtBu) -OH, 0.30 g of Fmoc-L-Asn (Trt) -OH, 0.30 g of Fmoc-L-Asn (Trt ) -OH, 0.22 g of Fmoc-L-Glu (OtBu) -OH, 0.31 g of Fmoc-L-Gln (Trt) -OH, 0.17 g of Fmoc-L-Val-OH, 0 , 20 g of Fmoc-L-Thr (tBu) -OH, 0.15 g of Fmoc-Gly-OH, 0.17 g of Fmoc-L-Val-OH, 0.20 g of Fmoc-L-Thr ( tBu) -OH, 0.23 g of Fmoc-L-Tyr (tBu) -OH, 0.15 g of Fmoc-Gly-OH and 0.19 g of Fmoc-L-Phe-OH (0.5 mmol; 2.5 eq.) In the presence in each coupling of 76.5 mg of HOBt (0.5 mmol; 2.5 eq.) And 77.3 μί of DIPCDI (0.5 mmol; 2.5 eq.).

After the synthesis, the peptidyl resins obtained were washed with DMF (5 x 1 min), DCM (4 x 1 min), diethyl ether (4 x 1 min) and dried in vacuo. EXAMPLE 13

Obtaining Fmoc-L-Val-Glv-L-AsD (OtBu) -L-lle-L-Ala-L-Glu (OtBu) -AM-MBHA and Fmoc-L-Val-Glv-L-AsD (OtBu) -L-lle-L-Ala-L-Glu (OtBu) -0-2-CITñ-®

0.2 mmol (1 eq.) Of the aminoacyl-resins Fmoc-L-Glu (OtBu) -AM-MBHA and Fmoc-L-Glu (OtBu) -0-2-CITrt-® were washed and unprotected as described in general methods to incorporate the following amino acids. On each of the two resins and following the described protocols, 0.16 g of Fmoc-L-Ala-OH, 0.18 g of Fmoc-L-lle-OH, 0.21 g of Fmoc-L were sequentially coupled. -Asp (OtBu) -OH, 0.15 g of Fmoc-Gly-OH and 0.17 g of Fmoc-L-Val-OH (0.5 mmol; 2.5 eq.) In the presence at each coupling of 76 , 5 mg of HOBt (0.5 mmol; 2.5 eq.) And 77.3 μΙ_ of DIPCDI (0.5 mmol; 2.5 eq.).

EXAMPLE 14

Obtaining Fmoc-L-lle-L-Ala-L-Glu (OtBu) -L-Val-L-Gln (Trt) -L-Lvs (Boc) -AM-MBHA and Fmoc-¿.- // e- ¿.- / /a-¿.-G/Í/ Ofeü ---- \ a / -¿.-G / n 7f -¿.-¿. s eoc -0-2-C / 7f -®

0.2 mmol (1 eq.) Of the aminoacyl-resins Fmoc-L-Lys (Boc) -AM-MBHA and Fmoc-L-Lys (Boc) -0— 2-CITrt-® were washed and unprotected as described in general methods to incorporate the following amino acids. On each of the two resins and following the described protocols, 0.31 g of Fmoc-L-Gln (Trt) -OH, 0.17 g of Fmoc-L-Val-OH, 0.22 g of Fmoc-L-Glu (OtBu) -OH, 0.16 g of Fmoc-L-Ala-OH and 0.18 g of Fmoc-L-lle-OH (0.5 mmol; 2.5 eq.) In the presence in each coupling 76.5 mg of HOBt (0.5 mmol; 2.5 eq.) and 77.3 μί of DIPCDI (0.5 mmol; 2.5 eq.).

EXAMPLE 15

Obtaining Fmoc-L-Val-L-Gln (Trt) -L-Lys (Boc) -L ^ is (Trt) -L-Ala-L-Ser (tBu) -AM ¾ / Fmoc-L- \ a / -LG / n 7f -LL s eoc -LH / s 7f -¿ .- / /a-¿.-Se eÍ / -0-2-C / 7f -® 0.2 mmol (1 eq.) Of the aminoacyl-resins Fmoc-L-Ser (tBu) -AM-MBHA and Fmoc-L-Ser (tBu) -0-2-CITrt-® were washed and unprotected as described in general methods to incorporate the following amino acids. On each of the two resins and following the described protocols, 0.16 g of Fmoc-L-Ala-OH, 0.31 g of Fmoc-L-His (Trt) -OH, 0.23 g of were sequentially coupled Fmoc-L-Lys (Boc) -OH, 0.31 g of Fmoc-L-Gln (Trt) -OH and 0.17 g of Fmoc-L-Val-OH (0.5 mmol; 2.5 eq. ) in the presence of 76.5 mg of HOBt (0.5 mmol; 2.5 eq.) and 77.3 μ 77_ of DIPCDI (0.5 mmol; 2.5 eq.) in each coupling.

EXAMPLE 16

Obtaining Fmoc-L-Val-Glv-L-AsD (OtBu) -L-lle-L-Ala-L-Glu (OtBu) -L-Val-L-Gln (Trt) -

-L-Lvs (Boc) -L-His (Trt) -L-Ala-L-Ser (tBu) -AM-MBHA and_ Fmoc-L-Val-Glv-L-AsD (OtBu) -L-lle-

-L-Ala-L-Glu (OtBu) -L-Val-L-Gln (Trt) -L-Lvs (Boc) -L ^ is (Trt) - ^

0.2 mmol (1 eq.) Of the aminoacyl-resins Fmoc-L-Ser (tBu) -AM-MBHA and Fmoc-L-Ser (tBu) -0-2-CITrt-® were washed and unprotected as described in general methods to incorporate the following amino acids. On each of the two resins and following the described protocols, 0.16 g of Fmoc-L-Ala-OH, 0.31 g of Fmoc-L-His (Trt) -OH, 0.23 g of were sequentially coupled Fmoc-L-Lys (Boc) -OH, 0.31 g of Fmoc-L-Gln (Trt) -OH, 0.17 g of Fmoc-L-Val-OH, 0.22 g of Fmoc-L-Glu (OtBu) -OH, 0.16 g of Fmoc-L-Ala-OH, 0.18 g of Fmoc-L-lle-OH, 0.21 g of Fmoc-L-Asp (OtBu) -OH, 0, 15 g of Fmoc-Gly-OH and 0.17 g of Fmoc-L-Val-OH (0.5 mmol; 2.5 eq.) In the presence in each coupling of 76.5 mg of HOBt (0.5 mmol ; 2.5 eq.) And 77.3 μί of DIPCDI (0.5 mmol; 2.5 eq.).

EXAMPLE 17

Obtaining Fmoc-L-Arq (Pbf) -L-lle-L-Ala-L-Met-L-Gln (Trt) -L-Val-AM-MBHA and Fmoc-L-Ara (Pbf) -L-lle -L-Ala-L-Met-L-Gln (Trt) -L-Val-Q-2-CITrt-® 0.2 mmol (1 eq.) Of the amino-acyl resins Fmoc-L-Val-AM-MBHA and Fmoc-L-Val-O-2-CITrt-® were washed and deprotected as described in the general methods for incorporating The following amino acids. On each of the two resins and following the described protocols, 0.31 g of Fmoc-L-Gln (Trt) -OH, 0.19 g of Fmoc-L-Met-OH, 0.16 g of Fmoc-L-Ala-OH, 0.18 g of Fmoc-L-lle-OH and 0.32 g of Fmoc-L-Arg (Pbf) -OH (0.5 mmol; 2.5 eq.) In the presence in each coupling of 76.5 mg of HOBt (0.5 mmol; 2.5 eq.) and 77.3 μΙ_ of DIPCDI (0.5 mmol; 2.5 eq.).

EXAMPLE 18

Obtaining Fmoc-L-Val-Glv-L-AsD (OtBu) -L-lle-L-Ala-L-Glu (OtBu) -L-Val-L-Gln (Trt) - -L-Lvs (Boc) -L-His (mL-Ala-L-Ser (tBu) -L-Leu-L-Lvs (B

-L-Gln (Trt) -L-Val-AM-MBHA y_

Fmoc-L-Val-Glv-L-AsD (OtBu) -L-lle-L-Ala-L-Glu (OtBu) -L-Val- -L-Gln (mL-Lvs (Boc) -L-His ( mL-Ala-L-Ser (tBu) -L-Leu-L ^

Ala- -L-Met-L-Gln (Trt) -L-Val-Q-2-CITrt-®

0.2 mmol (1 eq.) Of the amino-acyl resins Fmoc-L-Val-AM-MBHA and Fmoc-L-Val-O-2-CITrt-® were washed and deprotected as described in the general methods for incorporating The following amino acids. On each of the two resins and following the described protocols, 0.31 g of Fmoc-L-Gln (Trt) -OH, 0.19 g of Fmoc-L-Met-OH, 0.16 g of Fmoc-L-Ala-OH, 0.18 g of Fmoc-L-lle-OH, 0.32 g of Fmoc-L-Arg (Pbf) -OH, 0.23 g of Fmoc-L-Lys (Boc) -OH, 0.18 g of Fmoc-L-Leu-OH, 0.19 g of Fmoc-L-Ser (tBu) -OH, 0.16 g of Fmoc-L-Ala-OH, 0.31 g of Fmoc-L-His (Trt) -OH, 0.23 g of Fmoc-L-Lys (Boc) -OH, 0.31 g of Fmoc-L-Gln (Trt) -OH, 0.17 g of Fmoc- L-Val-OH, 0.22 g of Fmoc-L-Glu (OtBu) -OH, 0.16 g of Fmoc-L-Ala-OH, 0.18 g of Fmoc-L-lle-OH, 0, 21 g of Fmoc-L-Asp (OtBu) -OH, 0.15 g of Fmoc-Gly-OH and 0.17 g of Fmoc-L-Val-OH (0.5 mmol; 2.5 eq.) In presence in each coupling of 76.5 mg of HOBt (0.5 mmol; 2.5 eq.) and 77.3 μί of DIPCDI (0.5 mmol; 2.5 eq.).

After the synthesis, the peptidyl resins obtained were washed with DMF (5 x 1 min), DCM (4 x 1 min), diethyl ether (4 x 1 min) and dried in vacuo. EXAMPLE 19

General procedure for deprotection of the N-terminal Fmoc protective group

The Fmoc / V-terminal group was deprotected from the peptidyl resins obtained in Examples 2 to 18 as described in the general methods (20% piperidine in DMF, 1 x 5 min followed by 1 x 20 min). Subsequently, the peptidyl resins were washed with DMF (5 x 1 min), DCM (4 x 1 min), diethyl ether (4 x 1 min) and dried in vacuo.

EXAMPLE 20

Introduction procedure of palmitoyl group: Obtaining N-palmitoyl-peptidyl-resins

On 0.05 mmol of the peptidyl resins obtained in Example 19, 0.13 g of palmitic acid (0.5 mmol; 10 eq.) Predisolved in DMF (1 mL) was incorporated, in the presence of 76.5 mg of HOBt (1 mmol; 10 eq.) and 77.3 μΙ_ of DIPCDI (1 mmol; 10 eq.). They were allowed to react for 15 hours, after which the peptidyl resins were washed with THF (5 x 1 min), DCM (5 x 1 min), DMF (5 x 1 min), MeOH (5 x 1 min), DMF (5 x 1 min), THF (5 x 1 min), DMF (5 x 1 min), DCM (4 x 1 min), ether (3 x 1 min), and dried under vacuum.

EXAMPLE 21

Procedure for introducing acetyl group: Obtaining N-acetyl-peptidyl-resins

0.05 mmol of the peptidyl resins obtained in Example 19 were treated with 28.6 μΙ of acetic anhydride (0.5 mmol; 10 eq.) In the presence of 10 eq. of DIEA (87.1 μΙ_; 0.5 mmol) using 0.5 mL of DMF as solvent. They were allowed to react for 30 min, after which the peptidyl resins were washed with DMF (5 x 1 min), DCM (4 x 1 min), diethyl ether (4 x 1 min) and dried in vacuo.

EXAMPLE 22

Process of excision of the polymeric support and obtaining the peptides. 0.05 mmol of the dried peptidyl resins obtained in Examples 19, 20 and 21 were treated with 0.5 mL of TFA-TIS-H ₂ 0 (90: 5: 5) for 2 h at room temperature with stirring. The filtrates were collected on 5 mL cold diethyl ether, filtered through polypropylene syringes equipped with porous polyethylene discs and washed 5 times with 5 mL of diethyl ether. The final precipitates were dried in vacuo.

HPLC analysis in MeCN gradients (+ 0.07% TFA) in H ₂ 0 (+ 0.1% TFA) of the peptides obtained showed a purity greater than 85% in all cases. The identity of the peptides obtained was confirmed by ES-MS and the results are shown in the following table (Table 3).

PEPTIDE (M + H) ⁺ (M + H) ⁺ theoretical experim.

H- -MGETVN-NH ₂ (SEQ ID NO: 1 -NH ₂ ) 649.73 649.69

H- -NKIAQES-NH ₂ (SEQ ID NO: 2-NH ₂ ) 788.87 788.84

H- -MGETVNKIAQES-NH ₂ (SEQ ID NO: 16-NH ₂ ) 1306.46 1306.94

H- -IWKLQR-NH ₂ (SEQ ID NO: 3-NH ₂ ) 843.05 843.03

H- -MGETVNKIAQE-NH ₂ (SEQ ID NO: 21 -NH ₂ ) 1219.39 1219.36

H- -MGETVNKIAQESKNIWKLQRA-NH ₂ (SEQ ID NO: 17-NH ₂ ) 2444.83 2445.05

H- -FGYTVG-NH ₂ (SEQ ID NO: 5-NH ₂ ) 642.72 642.48

H- -TVQENN-NH ₂ (SEQ ID NO: 7-NH ₂ ) 702.73 702.70

H- -FGYTVGTVQE N NN H ₂ (SEQ ID NO: 31 -NH ₂ ) 1327.42 1327.1 1

H- -NDQVWK-NH ₂ (SEQ ID NO: 8-NH ₂ ) 788.87 788.85

H- -FGYTVGTVQE NN DQVWKFQR-N H ₂ (SEQ ID NO: 32-NH ₂ ) 2416.62 2416.95

H- -VGDIAE-NH ₂ (SEQ ID NO: 9-NH ₂ ) 602.65 602.70

H- -IAEVQK-NH ₂ (SEQ ID NO: 10-NH ₂ ) 686.82 686.79

H- -VQKHAS-NH ₂ (SEQ ID NO: 1 1 -NH ₂ ) 668.76 668.91

H- -VGDIAEVQKHAS-NH ₂ (SEQ ID NO: 33-NH ₂ ) 1253.38 1253.73

H- -RIAMQV-NH ₂ (SEQ ID NO: 12-NH ₂ ) 716.91 716.80

H- -VGDIAEVQKHASLKRIAMQV-NH ₂ (SEQ ID NO: 34-NH ₂ ) 2193.19 2193.16

H- -MGETVN-OH (SEQ ID NO: 1) 650.72 650.67

H- -NKIAQES-OH (SEQ ID NO: 2) 789.86 789.98

H- -MGETVNKIAQES-OH (SEQ ID NO: 16) 1307.45 1307.60

H- -IWKLQR-OH (SEQ ID NO: 3) 844.04 844.32

H- -MGETVNKIAQE-OH (SEQ ID NO: 21) 1220.38 1220.60

H- -MGETVNKIAQESKNIWKLQRA-OH (SEQ ID NO: 17) 2445.82 2446.72 H-FGYTVG-OH (SEQ ID NO: 5) 643.71 643.68

H-TVQENN-OH (SEQ ID NO: 7) 703.72 703.70

H - F G YTVGTVQ E N N -0 H (SEQ ID NO: 31) 1328.41 1328.86

H-NDQVWK-OH (SEQ ID NO: 8) 789.86 789.83

H-FGYTVGTVQENNDQVWKFQR-OH (SEQ ID NO: 32) 2417.61 2417.89

H-VGDIAE-OH (SEQ ID NO: 9) 603.64 603.53

H-IAEVQK-OH (SEQ ID NO: 10) 687.81 687.89

H-VQKHAS-OH (SEQ ID NO: 1 1) 669.75 670.39

H-VGDIAEVQKHAS-OH (SEQ ID NO: 33) 1254.37 1254.34

H-RIAMQV-OH (SEQ ID NO: 12) 717.90 717.88

H-VGDIAEVQKHASLKRIAMQV-OH (SEQ ID NO: 34) 2194.18 2193.81

Ac-MGETVN-NH ₂ (Acetyl-SEQ ID NO: 1 -NH ₂ ) 691, 77 691, 76

Ac-NKIAQES-NH ₂ (Acetyl-SEQ ID NO: 2-NH ₂ ) 830.91 830.89

Ac-MGETVNKIAQES-NH ₂ (Acetyl-SEQ ID NO: 16-NH ₂ ) 1348.50 1348.44

Ac-IWKLQR-NH ₂ (Acetyl-SEQ ID NO: 3-NH ₂ ) 885.09 885.21

Ac-MGETVNKIAQE-NH ₂ (Acetyl-SEQ ID NO: 21 -NH ₂ ) 1261, 43 1261, 40

Ac-MGETVNKIAQESKNIWKLQRA-NH ₂ (Acetyl-SEQ ID NO: 17-NH ₂ ) 2486.87 2487.35

Ac-FGYTVG-NH ₂ (Acetyl-SEQ ID NO: 5-NH ₂ ) 684.76 684.73

Ac-TVQENN-NH ₂ (Acetyl-SEQ ID NO: 7-NH ₂ ) 744.77 744.90

Ac-FGYTVGTVQE N NN H ₂ (Acetyl-SEQ ID NO: 31 -NH ₂ ) 1369.46 1369.40

Ac-NDQVWK-NH ₂ (Acetyl-SEQ ID NO: 8-NH ₂ ) 830.91 830.87

Ac-FGYTVGTVQE NN DQVWKFQR-N H ₂ (Acetyl-SEQ ID NO: 32-NH ₂ ) 2458.66 2458.83

Ac-VGDIAE-NH ₂ (Acetyl-SEQ ID NO: 9-NH ₂ ) 644.69 645.00

Ac-IAEVQK-NH ₂ (Acetyl-SEQ ID NO: 10-NH ₂ ) 728.86 728.60

Ac-VQKHAS-NH ₂ (Acetyl-SEQ ID NO: 1 1 -NH ₂ ) 710.80 710.77

Ac-VGDIAEVQKHAS-NH ₂ (Acetyl-SEQ ID NO: 33-NH ₂ ) 1295.42 1295.36

Ac-RIAMQV-NH ₂ (Acetyl-SEQ ID NO: 12-NH ₂ ) 758.95 759.17

Ac-VGDIAEVQKHASLKRIAMQV-NH ₂ (Acetyl-SEQ ID NO: 34-NH ₂ ) 2235.23 2235.38

Ac-MGETVN-OH (Acetyl-SEQ ID NO: 1) 692.76 692.96

Ac-NKIAQES-OH (Acetyl-SEQ ID NO: 2) 831, 90 831, 63

Ac-MGETVNKIAQES-OH (Acetyl-SEQ ID NO: 16) 1349.49 1349.71

Ac-IWKLQR-OH (Acetyl-SEQ ID NO: 3) 886.08 886.25

Ac-MGETVNKIAQE-OH (Acetyl-SEQ ID NO: 21) 1262.42 1262.40

Ac-MGETVNKIAQESKNIWKLQRA-OH (Acetyl-SEQ ID NO: 17) 2487.86 2487.55

Ac-FGYTVG-OH (Acetyl-SEQ ID NO: 5) 685.75 686.06 Ac-TVQENN-OH (Acetyl-SEQ ID NO: 7) 745.76 745.73

Ac-FGYTVGTVQENN-OH (Acetyl-SEQ ID NO: 31) 1370.45 1370.93

Ac-NDQVWK-OH (Acetyl-SEQ ID NO: 8) 831, 90 832.08

Ac-FGYTVGTVQENNDQVWKFQR-OH (Acetyl-SEQ ID NO: 32) 2459.65 2459.66

Ac-VGDIAE-OH (Acetyl-SEQ ID NO: 9) 645.68 645.65

Ac-IAEVQK-OH (Acetyl-SEQ ID NO: 10) 729.85 730.20

Ac-VQKHAS-OH (Acetyl-SEQ ID NO: 1 1) 71 1, 79 71 1, 76

Ac-VGDIAEVQKHAS-OH (Acetyl-SEQ ID NO: 33) 1296.41 1296.63

Ac-RIAMQV-OH (Acetyl-SEQ ID NO: 12) 759.94 759.95

Ac-VGDIAEVQKHASLKRIAMQV-OH (Acetyl-SEQ ID NO: 34) 2236.22 2236.20

Palm-MGETVN-NH ₂ (Palmitoil-SEQ ID NO: 1 -NH ₂ ) 888.14 887.88

Palm-NKIAQES-NH ₂ (Palmitoil-SEQ ID NO: 2-NH ₂ ) 1027.28 1027.73

Palm-MGETVNKIAQES-NH ₂ (Palmitoil-SEQ ID NO: 16-NH ₂ ) 1544.87 1544.84

Palm-IWKLQR-NH ₂ (Palmitoil-SEQ ID NO: 3-NH ₂ ) 1081, 46 1081, 19

Palm-MGETVNKIAQE-NH ₂ (Palmitoil-SEQ ID NO: 21 -NH ₂ ) 1457.80 1457.43

Palm-MGETVNKIAQESKNIWKLQRA-NH ₂ (Palmitoil-SEQ ID NO: 17-NH ₂ ) 2683.24 2683.04

Palm-FGYTVG-NH ₂ (Palmitoil-SEQ ID NO: 5-NH ₂ ) 881, 13 881, 02

Palm-TVQENN-NH ₂ (Palmitoil-SEQ ID NO: 7-NH ₂ ) 941, 14 941, 1 1

Palm-FGYTVGTVQENN-NH ₂ (Palmitoil-SEQ ID NO: 31 -NH ₂ ) 1565.83 1565.63

Palm-NDQVWK-NH ₂ (Palmitoil-SEQ ID NO: 8-NH ₂ ) 1027.28 1027.24

Palm-FGYTVGTVQENNDQVWKFQR-NH ₂ (Palmitoil-SEQ ID NO: 32-NH ₂ ) 2655.03 2655.00

Palm-VGDIAE-NH ₂ (Palmitoil-SEQ ID NO: 9-NH ₂ ) 841, 06 840.69

Palm-IAEVQK-NH ₂ (Palmitoil-SEQ ID NO: 10-NH ₂ ) 925.23 925.21

Palm-VQKHAS-NH ₂ (Palmitoil-SEQ ID NO: 1 1 -NH ₂ ) 907.17 907.45

Palm-VGDIAEVQKHAS-NH ₂ (Palmitoil-SEQ ID NO: 33-NH ₂ ) 1491, 79 1491, 84

Palm-RIAMQV-NH ₂ (Palmitoil-SEQ ID NO: 12-NH ₂ ) 955.32 955.06

Palm-VGDIAEVQKHASLKRIAMQV-NH ₂ (Palmitoil-SEQ ID NO: 34-NH ₂ ) 2431, 60 2431, 61

Palm-MGETVN-OH (Palmitoil-SEQ ID NO: 1) 889.13 889.77

Palm-NKIAQES-OH (Palmitoil-SEQ ID NO: 2) 1028.27 1028.44

Palm-MGETVNKIAQES-OH (Palmitoil-SEQ ID NO: 16) 1545.86 1545.77

Palm-IWKLQR-OH (Palmitoil-SEQ ID NO: 3) 1082.45 1082.42

Palm-MGETVNKIAQE-OH (Palmitoil-SEQ ID NO: 21) 1458.79 1459.30

Palm-MGETVNKIAQESKNIWKLQRA-OH (Palmitoil-SEQ ID NO: 17) 2684.23 2683.63

Palm-FGYTVG-OH (Palmitoil-SEQ ID NO: 5) 882.12 882.30

Palm-TVQENN-OH (Palmitoil-SEQ ID NO: 7) 942.13 942.21 Palm-FGYTVGTVQENN-OH (Palmitoil-SEQ ID NO: 31) 1566.82 1566.55

Palm-NDQVWK-OH (Palmitoil-SEQ ID NO: 8) 1028.27 1028.75

Palm-FGYTVGTVQENNDQVWKFQR-OH (Palmitoil-SEQ ID NO: 32) 2656.02 2655.68

Palm-VGDIAE-OH (Palmitoil-SEQ ID NO: 9) 842.05 842.17 Palm-IAEVQK-OH (Palmitoil-SEQ ID NO: 10) 926.22 926.55

Palm-VQKHAS-OH (Palmitoil-SEQ ID NO: 1 1) 908.16 908.24

Palm-VGDIAEVQKHAS-OH (Palmitoil-SEQ ID NO: 33) 1492.78 1492.91

Palm-RIAMQV-OH (Palmitoil-SEQ ID NO: 12) 956.31 956.95

Palm-VGDIAEVQKHASLKRIAMQV-OH (Palmitoil-SEQ ID NO: 34) 2432.59 2432.25

Table 3

EXAMPLE 23

Polymeric support cleavage procedure and derivatization of the C-terminal end of the peptides with hexadecylamine

25 mg of the / V-acetyl-peptidyl-0-2-CITrt-resins obtained in Example 21, previously dried under vacuum in the presence of KOH, were treated with 0.5 mL of a 3% solution of TFA in DCM for 5 min to obtain the corresponding peptides with the fully protected side chains. The filtrates were collected on 10 mL of cold diethyl ether and the treatment was repeated three times. The ethereal solutions were evaporated under reduced pressure at dryness and at room temperature, the precipitates were resuspended in 50% MeCN in H ₂ 0 and lyophilized. 5 mg of the peptide crude obtained were weighed in a balloon, 3 eq. of hexadecylamine and 25 mL of anhydrous DMF. 2 eq. From DIPCDI, and allowed to react with magnetic stirring at 47 ° C. The reactions were monitored by HPLC by disappearance of the initial products, being complete after 24-48 h. The solvents were evaporated under reduced pressure to dryness and coevaporated twice with DCM. The obtained residues, corresponding to the peptides with the fully protected and amidated side chains at their C-terminal end, were resuspended in 5 mL of a mixture of TFA-DCM-anisole (49: 49: 2) and allowed to react for 30 min at room temperature. 50 mL of cold diethyl ether was added, the solvents were evaporated under reduced pressure and two additional coevaporations were performed with ether. The residues were dissolved in a 50% mixture of MeCN in H ₂ 0 and lyophilized. HPLC analysis in MeCN gradients (+ 0.07% TFA) in H ₂ 0 (+ 0.1% TFA) of the peptides obtained showed a purity greater than 60% in all cases. The identity of the peptides obtained was confirmed by ES-MS and the results are shown in the following table (Table 4).

PEPTIDE (M + H) ⁺ (M + H) ⁺ experimental theory

Ac-MGETVN-NH- (CH ₂ ) and ₅ CH ₃

(Acetyl-SEQ ID NO: 1 -NH- (CH ₂ ) ₁₅ CH ₃ ) 916.20 916.25 Ac-NKIAQES-NH- (CH ₂ ) and ₅ CH ₃

(Acetyl-SEQ ID NO: 2-NH- (CH ₂ ) ₁₅ CH ₃ ) 1055.34 1055.62

Ac-MGETVNKIAQES-NH- (CH ₂ ) ₁₅ CH ₃

(Acetyl-SEQ ID NO: 16-NH- (CH ₂ ) ₁₅ CH ₃ ) 1572.93 1572.58

Ac-IWKLQR-NH- (CH ₂ ) ₁₅ CH ₃

(Acetyl-SEQ ID NO: 3-NH- (CH ₂ ) ₁₅ CH ₃ ) 1 109.52 1 108.94

Ac-MGETVNKIAQE-NH- (CH ₂ ) ₁₅ CH ₃

(Acetyl-SEQ ID NO: 21 -NH- (CH ₂ ) ₁₅ CH ₃ ) 1485.86 1485.99

Ac-MGETVNKIAQESKNIWKLQRA-NH- (CH ₂ ) ₁₅ CH ₃

(Acetyl-SEQ ID NO: 17-NH- (CH ₂ ) ₁₅ CH ₃ ) 271 1, 30 271 1, 54 Ac-FGYTVG-NH- (CH ₂ ) ₁₅ CH ₃

(Acetyl-SEQ ID NO: 5-NH- (CH ₂ ) ₁₅ CH ₃ ) 909.19 909.01

Ac-TVQENN-NH- (CH ₂ ) ₁₅ CH ₃

(Acetyl-SEQ ID NO: 7-NH- (CH ₂ ) ₁₅ CH ₃ ) 969.20 969.66

Ac-FGYTVGTVQENN-NH- (CH ₂ ) ₁₅ CH ₃

(Acetyl-SEQ ID NO: 31 -NH- (CH ₂ ) ₁₅ CH ₃ ) 1593.89 1593.88

Ac-NDQVWK-NH- (CH ₂ ) ₁₅ CH ₃

(Acetyl-SEQ ID NO: 8-NH- (CH ₂ ) ₁₅ CH ₃ ) 1055.34 1055.55

Ac-FGYTVGTVQENNDQVWKFQR-NH- (CH ₂ ) ₁₅ CH ₃

(Acetyl-SEQ ID NO: 32-NH- (CH ₂ ) ₁₅ CH ₃ ) 2683.09 2683.43 Ac-VGDIAE-NH- (CH ₂ ) ₁₅ CH ₃

(Acetyl-SEQ ID NO: 9-NH- (CH ₂ ) ₁₅ CH ₃ ) 869.12 869.03

Ac-IAEVQK-NH- (CH ₂ ) ₁₅ CH ₃

(Acetyl-SEQ ID NO: 10-NH- (CH ₂ ) ₁₅ CH ₃ ) 953.29 953.34

Ac-VQKHAS-NH- (CH ₂ ) ₁₅ CH ₃

(Acetyl-SEQ ID NO: 1 1 -NH- (CH ₂ ) ₁₅ CH ₃ ) 935.23 935.98 Ac-VGDIAEVQKHAS-NH- (CH ₂ ) and ₅ CH ₃

(Acetyl-SEQ ID NO: 33-NH- (CH ₂ ) ₁₅ CH ₃ ) 1519.85 1520.22 Ac-RIAMQV-NH- (CH ₂ ) and ₅ CH ₃

(Acetyl-SEQ ID NO: 12-NH- (CH ₂ ) ₁₅ CH ₃ ) 983.38 983.51 Ac-VGDIAEVQKHASLKRIAMQV-NH- (CH ₂ ) ₁₅ CH ₃

(Acetyl-SEQ ID NO: 34-NH- (CH ₂ ) ₁₅ CH ₃ ) 2459.66 2459.35

Table 4

EXAMPLE 24

Inhibition of receptor activity by peptides derived from TRPV1

The inhibitory activity of the peptides obtained in Examples 22 and

23 in SH-SY5Y neuroblastoma cells, which express rat TRPV1 stably (SH-SY5Y-TRPV1), by monitoring Ca ²⁺ signals induced by capsaicin by microfluorography using a fluorescence plate reader. SH-SY5Y-TRPV1 cells were cultured in Earle's minimum medium (MEM) containing 10% (v / v) fetal calf serum (FCS), supplemented with 1% non-essential amino acids, 2 mM L-glutamine, 100 μg mL streptomycin, 100 U / mL penicillin and 0.4 μg / mL puromycin. The cells were grown in an incubator with a humid atmosphere at 37 ° C and 5% C0 ₂ . The cells were dispersed by enzymatic methods and seeded in 96-well plates. Cells were incubated with the peptides at 10 μΜ for 1 h and subsequently treated with 5 μΜ Fluo-4 acetoxymethyl ester in the presence of 0.02% resuspended pluronic acid in Hank's balanced saline solution (HBSS: 140 mM NaCI, 4 mM KCI, 1 mM MgCI ₂ , 1.8 mMCaCI ₂ , 5 mM D-glucose, 10 mM HEPES, pH 7.4) for 40-50 min at 37 ° C, after which they were transferred to a plate reader fluorescence. TRPV1 activation was performed with a pulse of 10 μΜ of capsaicin with a microinjector for 10 s. The Fluo-4 probe was excited at 500 nm and the emitted fluorescence was filtered with a 535 nm filter. In the measurements of the Ca ²⁺ signals induced by capsaicin, the measurements were normalized with respect to the activity of the receptor in the absence of peptides (vehicle, 0.1% DMSO).

Alternatively, the inhibitory activity of the peptides of the invention was evaluated in SH-SY5Y-TRPV1 cells by electrophysiology. Cultured cells were dispersed by enzymatic methods and seeded at low density in 33 mm diameter Petri dishes to perform electrophysiological recordings. Membrane currents and voltages were recorded by electrophysiological membrane clamping techniques using the total current recording configuration [García-Sanz N. et al. (2004) J. Neurosci. 24: 5307-5314; Valente P et al. (2008) FASEB J. 22: 3298-3309]. For the SH-SY5Y-TRPV1 cell registration, the pipette solution consisted of 150 mM NaCI, 3 mM MgCI ₂ , 5 mM EGTA and 10 mM HEPES pH 7.2 adjusted with NaOH and the bath solution consisted of 150 mM NaCI, 6 mM CsCI, 1 mM MgCI ₂ , 1.5 mM CaCI ₂ , 10 mM D-glucose and 10 mM HEPES pH 7.4 adjusted with CsOH. TRPV1 activation was performed with pulses of 10 μΜ capsaicin for 10 s, using a manual gravity perfusion system. The log pipettes were prepared from thin-walled borosilicate glass capillaries (World Precision Instruments, Sarasota, FL), stretched with a horizontal stretcher (P-97, Sutter Ins. Co., Novato, CA) until obtaining a 2-4 Ω resistance. Data were recorded by filtering at 10 kHz (EPC10 amplifier and software from HEKA electronics, Lambrecht, Germany or Multiclamp amplifier, pClamp software and a 1322A Digidata digitizer from Molecular Devices, Palo Alto, California) and filtering at 3 kHz for analysis ( 8.54 PulseFit, HEKA; Origin 7.5, pClamp9, WinASCD software by G. Droogmans, Katholieke Universiteit Leuven, and OriginLab Corp., Southampton MA). The pipette resistance was generally less than 10 Ω and to minimize the errors in the voltage it was compensated at 60-80%. All measurements were made at 20-21 ° C. The measurements were normalized with respect to receptor activity in the absence of peptides (vehicle, 0.1% DMSO).

The following table (Table 5) details the TRPV1 activity values for those peptides that showed TRPV1 activity inhibition values greater than 15%. The data represent the mean ± sem, with n (number of measurements) = 9, in three independent experiments. The most potent peptide was the Palmitoil-SEQ ID NO: 16-NH ₂ peptide. which blocked the TRPV1 receiver by 80%.

TRPV1 ACTIVITY PEPTIDE (%)

100 ± 6 vehicle

Palmitoil-SEQ ID NO: 16-NH ₂ 20 ± 7

Acetyl-SEQ ID NO: 16-NH ₂ 28 ± 6

Acetyl-SEQ ID NO: 16-NH- (CH ₂ ) ₁₅ CH ₃ 38 ± 8

Palmitoil-SEQ ID NO: 21 -NH ₂ 40 ± 10

Palmitoil-SEQ ID NO: 16 40 ± 8 Acetyl-SEQ ID NO: 16 49 ± 3

Palmitoil-SEQ ID NO: 22-NH ₂ 50 ± 9

Palmitoil-SEQ ID NO: 17-NH ₂ 55 ± 8

Palmitoil-SEQ ID NO: 15-NH ₂ 64 ± 6

Palmitoil-SEQ ID NO: 23-NH ₂ 65 ± 6

SEQ ID NO: 16-NH ₂ 65 ± 2

Palmitoil-SEQ ID NO: 25-NH ₂ 68 ± 10

Palmitoil-SEQ ID NO: 28-NH ₂ 70 ± 13

Palmitoil-SEQ ID NO: 3-NH ₂ 72 ± 6

Palmitoil-SEQ ID NO: 29-NH ₂ 72 ± 12

SEQ ID NO: 16 72 ± 4

Palmitoil-SEQ ID NO: 1 -NH ₂ 73 ± 4

Palmitoil-SEQ ID NO: 30-NH ₂ 74 ± 6

Palmitoil-SEQ ID NO: 24-NH ₂ 75 ± 9

Palmitoil-SEQ ID NO: 2-NH ₂ 75 ± 10

Palmitoil-SEQ ID NO: 18-NH ₂ 80 ± 9

Palmitoil-SEQ ID NO: 19-NH ₂ 80 ± 1 1

Palmitoil-SEQ ID NO: 14-NH ₂ 81 ± 6

Palmitoil-SEQ ID NO: 26-NH ₂ 85 ± 9

Palmitoil-SEQ ID NO: 27-NH ₂ 85 ± 1 1

Palmitoil-SEQ ID NO: 20-NH ₂ 85 ± 14

Table 5

EXAMPLE 25

Inhibition of TRPM8 receptor activity by TRPM8 derived peptides

The inhibitory activity of the peptides of the invention in the human embryonic kidney cell line HEK293, which stably expresses the rat TRPM8 receptor (HEK293-TRPM8), was evaluated by monitoring Ca ²⁺ signals induced by menthol using a fluorescence plate reader. HEK293-TRPM8 cells were cultured in modified Dulbecco Eagle (DMEM) medium, supplemented with 10% (v / v) FCS, 100 μg / mL streptomycin and 100 U / mL penicillin, and 0.2 mg / mL geneticin . The cells were grown in an incubator with a humid atmosphere at 37 ° C and 5% C0 ₂ . The cells were dispersed by enzymatic methods and seeded in 96-well plates. The cells were incubated with the peptides at 10 μΜ for 1 h and subsequently treated with 5 μΜ Fluo-4 acetoxymethyl ester in the presence of 0.02% resuspended pluronic acid in Hank's balanced saline solution (HBSS: 140 mM NaCI, 4 mM KCI, 1 mM MgCI ₂ , 1, 8 mMCaCI _2.5 mM D-glucose, 10 mM HEPES, pH 7.4) for 40-50 min at 37 ° C, after which they were transferred to a fluorescence plate reader. TRPM8 activation was performed with a 100 μ un pulse of menthol at 30 ° C with a microinjector for 10 s. The Fluo-4 probe was excited at 500 nm and the emitted fluorescence was filtered with a 535 nm filter. The ionic channel activity was calculated as the difference in fluorescence signal between the baseline (before the addition of menthol) and the fluorescent signal after the agonist was added. The measurements were normalized with respect to receptor activity in the absence of peptides (vehicle, 0.1% DMSO).

Alternatively, the inhibitory activity of the peptides of the invention was evaluated in the HEK293-TRPM8 cells by electrophysiology, following the method described in Example 24 and using 100 μΜ pulses of menthol at 30 ° C instead of capsaicin to activate the receptor TRPM8. Measurements of channel activity were normalized with respect to receptor activity in the absence of peptides (vehicle, 0.1% DMSO).

The following table (Table 6) details the TRPM8 activity values for those peptides that showed TRPM8 activity inhibition values greater than 15%. The data represent the mean ± sem, with n (number of measurements) = 9, in three independent experiments. The most potent peptide was the peptide palmitoyl-SEQ ID NO: 31 -NH _2, the TRPM8 receptor blocked by 62%.

PEPTID ACTIVITY OF TRPM8 (%)

100 ± 0 vehicle

Palmitoil-SEQ ID NO: 31 -NH ₂ 38 ± 1

Palmitoil-SEQ ID NO: 32-NH ₂ 41 ± 1 1

Acetyl-SEQ ID NO: 31 -NH ₂ 45 ± 5

Acetyl-SEQ ID NO: 31 -NH- (CH ₂ ) ₁₅ CH ₃ 46 ± 7

Palmitoil-SEQ ID NO: 31 53 ± 7

Palmitoil-SEQ ID NO: 5-NH ₂ 65 ± 9

Acetyl-SEQ ID NO: 31 67 ± 9

Palmitoil-SEQ ID NO: 8-NH ₂ 68 ± 6

Palmitoil-SEQ ID NO: 7-NH ₂ 70 ± 13 SEQ ID NO: 31 -NH ₂ 76 ± 4

SEQ ID NO: 31 82 ± 6

Table 6

EXAMPLE 26

Inhibition of TRPA 1 receptor activity by peptides derived from TRPA 1

The inhibitory activity of the peptides of the invention in the Chinese hamster ovary cell line CHO, which stably expresses the mouse TRPA1 receptor (CHO-TRPA1), was monitored by monitoring Ca ²⁺ signals induced by cinnamaldehyde using a fluorescence plate reader. CHO-TRPA1 cells were cultured in modified Dulbecco Eagle medium (DMEM), supplemented with 10% (v / v) FCS, 100 μg mL streptomycin and 100 U / mL penicillin. The cells were grown in an incubator with a humid atmosphere at 37 ° C and 5% C0 ₂ . The cells were dispersed by enzymatic methods and seeded in 96-well plates. Cells were incubated with the peptides at 10 μΜ for 1 h and subsequently treated with 5 μΜ Fluo-4-acetoxymethyl ester in the presence of 0.02% resuspended pluronic acid in Hank's balanced salt solution (HBSS: 140 mM NaCI, 4 mM KCI, 1 mM MgCI ₂ , 1.8 mMCaCI ₂ , 5 mM D-glucose, 10 mM HEPES, pH 7.4) for 40-50 min at 37 ° C, after which they were transferred to a plate reader fluorescence. Activation of TRPA1 was performed with a pulse of 200 μΜ cinnamaldehyde at 25 ° C with a microinjector for 10 s. The calcium-sensitive probe Fluo-4 was excited at 500 nm and the emitted fluorescence was filtered with a 535 nm filter. The ionic channel activity was calculated as the difference in fluorescence signal between the baseline (before the addition of the cinnamaldehyde) and the fluorescent signal after the agonist was added. The measurements were normalized with respect to receptor activity in the absence of peptides (vehicle, 0.1% DMSO).

Alternatively, the inhibitory activity of the peptides of the invention was evaluated in the CHO-TRPA1 cells by electrophysiology, following the method described in Example 24 and using 200 μΜ cinnamaldehyde pulses at 25 ° C instead of capsaicin to activate the TRPA1 receptor . Measurements of channel activity were normalized with respect to receptor activity in the absence of peptides (vehicle, 0.1% DMSO). The following table (Table 7) details the TRPA1 activity values for those peptides that showed TRPA1 activity inhibition values greater than 15%. The data represent the mean ± sem, with n (number of measurements) = 9, in three independent experiments. The most potent peptide was the Palmitoil-SEQ ID NO: 33-NH ₂ peptide, which blocked the TRPA1 receptor by 47%.

PEPTIDE TRPA1 ACTIVITY (%)

100 ± 0 vehicle

Palmitoil-SEQ ID NO: 33-NH ₂ 53 ± 4

Acetyl-SEQ ID NO: 33-NH ₂ 56 ± 2

Palmitoil-SEQ ID NO: 34-NH ₂ 58 ± 3

Palmitoil-SEQ ID NO: 9-NH ₂ 59 ± 8

Palmitoil-SEQ ID NO: 1 1 -NH ₂ 61 ± 7

Acetyl-SEQ ID NO: 33-NH- (CH ₂ ) ₁₅ CH ₃ 61 ± 6

Palmitoil-SEQ ID NO: 33 62 ± 5

Palmitoil-SEQ ID NO: 10-NH ₂ 66 ± 12

Acetyl-SEQ ID NO: 33 70 ± 3

Palmitoil-SEQ ID NO: 12-NH ₂ 73 ± 9

SEQ ID NO: 33-NH ₂ 79 ± 7

SEQ ID NO: 33 86 ± 3

Table 7

EXAMPLE 27

Inhibition of TRPV1-mediated α-CGRP release in sensory neurons in culture

Activation of TRPV1 in peptidergic sensory neurons leads to the entry of Ca ²⁺ that activates intracellular signaling cascades and, concomitantly, leads to the release of pro-inflammatory peptides such as substance P and the peptide related to the gene of ocalcitonin (α-CGRP). Thus, the efficacy and potency of Palmitoil-SEQ ID NO: 16-NH ₂ in inhibiting the release of α-CGRP in rat DRG neurons in culture was evaluated.

Primary cultures of dorsal root ganglion neurons (DRG) were prepared from neonatal rats [Camprubi-Robles et al., (2009) FASEB J. 23: 3722-33]. Wistar rats 3-6 days old were anesthetized and sacrificed by decapitation. The spinal cord was dissected and the DRG neurons were removed and transferred to 2 mL of DMEM supplemented with collagenase IA. After digestion with collagenase at 37 ° C for 60 min, the cells were centrifuged for 5 min and resuspended in DMEM supplemented with 10% FBS. The cells were dispersed using 23 and 25 G needles and subsequently filtered through a 40 μηη filter. After centrifugation (1,000 rpm for 10 min), the cells were resuspended in DMEM supplemented with 10% FBS, 1% penicillin / streptomycin, 1% L-glutamine, 100 ng / mL NGF and 10 μΜ cytosine arabinoside , and seeded in crystals coated with laminin and polylysine. The cells were grown in an incubator at 37 ° C in a humid atmosphere with 5% C0 ₂ . All experiments were performed between the third and fourth day of cultivation.

Neural cultures were incubated with the Palmitoil-SEQ ID NO: 16-NH ₂ peptide at a concentration of 10 µΜ for 60 min, after which the release of α-CGRP was induced by treatment with 1 µΜ capsaicin for 5 min. Supernatants were collected and the amount of α-CGRP released was determined by an immunoenzymatic assay using a commercial CGRP detection kit (SPI-Bio, Société de Pharmacologie et d'lmmunologie-BIO, France, Ref. A05482) and measuring of absorbance at 405 nm. The intensity of the absorbance is proportional to the amount of α-CGRP released. The values were normalized with respect to the baseline release of CGRP from vehicle treated cells (0.1% DMSO), and are shown in Figure 1 as mean ± sem, with n (number of neurons) ≥25

The Palmitoyl-SEQ ID NO: 16-NH ₂ peptide inhibited the release of capsaicin-mediated a-CGRP by 59%.

EXAMPLE 28

In vivo inhibition of nerve activity induced by capsaicin

It was explored if the Palmitoil-SEQ ID NO: 16-NH ₂ peptide shows inhibitory activity of TRPV1 function in vivo. To this end, its effect on electrical discharges caused by harmful stimulation of sensory receptors present in polymodal terminations of nociceptor nerve fibers mediating painful signals in the knee joint was evaluated. Adult male rats of the Wistar variety (270-370 g; n = 1 1) were anesthetized and a catheter was inserted into the right saphenous artery for local intra-arterial administration of substances in the knee joint [Gomis A et al . (2007) Pain; 130: 126-36]. The proximal end of the saphenous nerve was dissected to obtain fine filaments. The nerve fibers that innervate the knee joint were identified by locating their recipient field, which was determined by the discharge of action potentials from the knee tissue and adjacent tissues in response to the pressure produced with a glass tip [ Gomis A et al. cited ad supra]. The mechanical stimuli consisted of rotations of the knee joint inward and outward in the ranges of harmful and normal movement with a duration of 10 s. The experiments shown include complete records in 20 filaments containing between two and five identifiable units.

In the rat's median articular nerve, about 80% of the multi-unit filaments that discharged in response to the harmful rotation of the knee joint were also excited by intra-arterial injection of capsaicin (Figure 2a). 100 µί doses of 10 µΜ capsaicin and prolonged intervals between injections (15 min) were used to reduce the known inactivation of nerve sensory fibers caused by repeated application of capsaicin. The impulse caused by capsaicin was virtually eliminated when 100 μί of Palmitoil-SEQ ID NO: 16-NH _{2 was administered} at 100 μΜ (Figures 2b-d). Intra-arterial injection of Palmitoil-SEQ ID NO: 16-NH ₂ , followed by washing with saline solution, gradually reduced (average time reduction of about 30 min) the impulse caused by subsequent administrations of capsaicin. Vehicle administration (DMSO) did not affect nerve activity caused by capsaicin or mechanical stimuli. Overall, these results imply that the Palmitoil-SEQ ID NO: 16-NH ₂ peptide exhibits anti-nociceptive activity in vivo by modulating the activity of the TRPV1 receptors.

EXAMPLE 29

In vivo inhibition of menthol-induced nerve activity

It was explored whether Palmitoyl-peptide SEQ ID NO: 31 showed inhibitory activity -NH ₂ function of TRPM8 in vivo. To this end, its effect on electrical discharges caused by harmful stimulation of sensory receptors was evaluated. present in polymodal endings of nociceptor nerve fibers mediating painful signals in the knee joint.

A group of 6 adult male rats of the Wistar variety (250-350 g) were anesthetized and subsequently a catheter was inserted into the right saphenous artery for local intraarterial administration of substances in the knee joint. The proximal end of the saphenous nerve was dissected to obtain fine filaments. The nerve fibers that innervate the knee joint were identified by the location of its receptor field, which was determined by the discharge of action potentials of the knee tissue and adjacent tissues in response to the pressure produced with a glass tip. The mechanical stimuli consisted of rotations of the knee joint inward and outward in the ranges of harmful and normal movement with a duration of 10 s [Gomis A. et al. (2007) Pain 130 (1-2): 126-136]. The experiments shown include complete records in 20 filaments containing between two and five identifiable units.

In the rat's median articular nerve, about 80% of the multi-unit filaments that discharged in response to the harmful rotation of the knee joint were further excited by intraarterial injection of menthol. 100 L doses of 100 μΜ menthol and prolonged intervals between injections (15 min) were used to minimize the inactivation of nerve sensory fibers caused by repeated menthol application. The impulse caused by menthol was virtually eliminated when 100 μί of Palmitoil-SEQ ID NO: 31-NH ₂ to 100 μΜ was administered (Table 8). The intra-arterial injection of Palmitoil-SEQ ID NO: 31 -NH ₂ , followed by washing with saline solution, gradually reduced (average time reduction of about 20 min) the impulse caused by subsequent administrations of menthol. Vehicle administration (DMSO) did not affect nerve activity caused by menthol or mechanical stimuli. Overall, these results imply that Palmitoyl-peptide SEQ ID NO: 31 exhibits -NH ₂ activity in vivo by modulating the activity of TRPM8 receptors. FIBER ACTIVITY PEPTIDE (%)

Vehicle 75 ± 6

Palmitoil-SEQ ID NO: 31 -NH ₂ 48 ± 9

Table 8

EXAMPLE 30 In vivo nerve activity inhibition induced by cinnamaldehyde.

It was explored if the Palmitoil-SEQ ID NO: 33-NH ₂ peptide showed inhibitory activity of TRPA1 function in vivo. To this end, its effect on electrical discharges caused by harmful stimulation of sensory receptors present in polymodal terminations of nociceptor nerve fibers mediating painful signals in the knee joint was evaluated.

A group of 4 adult male rats of the Wistar variety (250-350 g) were anesthetized and subsequently a catheter was inserted into the right saphenous artery for local intraarterial administration of substances in the knee joint. The proximal end of the saphenous nerve was dissected to obtain fine filaments. The nerve fibers that innervate the knee joint were identified by the location of its receptor field, which was determined by the discharge of action potentials of the knee tissue and adjacent tissues in response to the pressure produced with a glass tip. The mechanical stimuli consisted of rotations of the knee joint inward and outward in the ranges of harmful and normal movement with a duration of 10 s [Gomis A. et al. (2007) Pain 130 (1-2): 126-136]. The experiments shown include complete records in 20 filaments containing between two and five identifiable units.

In the rat's median articular nerve, about 80% of the multi-unit filaments that discharged in response to the harmful rotation of the knee joint were further excited by intra-arterial injection of cinnamaldehyde. 100 μί doses of 100 μΜ cinnamaldehyde and prolonged intervals between injections (15 min) were used to minimize the inactivation of nerve sensory fibers caused by repeated application of cinnamaldehyde. The impulse caused by cinnamaldehyde was virtually eliminated when 100 μί of Palmitoil-SEQ ID NO: 33-NH ₂ at 100 μΜ was administered (Table 9). The intra-arterial injection of Palmitoil-SEQ ID NO: 33-NH ₂ , followed by washing with saline solution, gradually reduced (average time reduction of about 20 min) the impulse caused by subsequent administrations of cinnamaldehyde. Vehicle administration (DMSO) did not affect nerve activity caused by cinnamaldehyde or mechanical stimuli. Overall, these results imply that the Palmitoil-SEQ ID NO: 33-NH ₂ peptide exhibits anti-nociceptive activity in vivo by modulating the activity of the TRPA1 receptors. FIBER ACTIVITY PEPTIDE (%)

Vehicle 83 ± 4

Palmitoil-SEQ ID NO: 33-NH ₂ 58 ± 8

Table 9

EXAMPLE 31

Attenuation of thermal hyperalgesia and mechanical allodynia produced by intraplantar invention of Freund's complete adjuvant (CFA).

The in vivo anti-nociceptive effect of the Palmitoil-SEQ ID NO: 16-NH ₂ compound was explored by evaluating the effect of thermal hyperalgesia and mechanical allodynia produced by plantar administration of CFA.

Wistar rats (200-300 g) were used for the study (n = 6). An emulsion of CFA (oil / saline solution 1: 1, 0.5 mg / ml) was injected into the plantar surface (50 μΙ_). Palmitoil-SEQ ID NO: 16-NH ₂ (5 mg / kg) or vehicle (DMSO) was administered intraperitoneally 24 h after CFA injection. Thermal hyperalgesia was monitored 24 hours after CFA injection and up to 6 hours after administering treatments with a dynamic plantar stesiometer from Ugo Basile as described in the literature [García-Martínez C. et al. (2006) J. Pain 7 (10): 735-746]. The rats were accustomed to an apparatus consisting of individual Perspex boxes on an elevated glass table. A mobile radiant heat source was placed under the table and focused on a rear leg. The leg withdrawal latencies were defined as the time it takes for the rat to remove its hind leg from the heat source. A 25-second cut-off point was set to avoid tissue damage. Mechanical allodynia was followed up to 48 h after administration of treatments (Palmitoil-SEQ ID NO: 16-NH ₂ at 5 mg / kg or vehicle) using Von Frey filaments with the "up and down" method [ García-Martínez C. et al. (2006) J. Pain 7 (10): 735-746]. The rats were placed on a raised wire mesh grid (6 x 6 mm ² openings) under plastic chambers. To quantify the mechanical sensitivity of the legs, filaments with different forces (in grams) were applied 10 times to the hind leg in an ascending order of strength. The frequency of withdrawal responses was monitored and represented as the percentage of response. The filament was applied for 1 to 2 seconds, with an interval between stimuli of 5 to 10 seconds. Data were also calculated as the area under the curve (AUC), and unilateral ANOVA was used followed by Dunnett's post hoc test as a statistical analysis. Statistical significance was set at p <0.05. The Graphpad Prism 5.0 software package was used for statistical analysis.

The results showed that Palmitoil-SEQ ID NO: 16-NH ₂ at 5 mg / kg significantly reduced thermal hyperalgesia and mechanical allodynia produced by CFA injection.

Homolateral Contralateral

Thermal Mechanical Mechanical Thermal

(AUC) (AUC) (AUC) (AUC)

Vehicle 54 ± 12 1750 ± 250 98 ± 14 572 ± 1 13

Palmitoil-SEQ ID NO: 16-NH ₂ 81 ± 19 780 ± 176 93 ± 1 1 605 ± 106

Statistically significant in YES YES No No comparison with the vehicle

(p <0.05)

Table 10

EXAMPLE 32

Inhibition of thermal hyperalgesia and itching-mediated scratching caused by bile duct ligation (BDL) in rats.

The in vivo anti-nociceptive activity of the Palmitoil-SEQ ID NO: 16-NH ₂ compound was further explored by evaluating the effect on thermal hyperalgesia and chronic pruritus caused by long-term bile duct ligation (BDL).

Male Wistar rats (200-250 g) were used for the study. Rats were operated by BDL as described in the literature [Jover R. et al. (2006) Hepatology 43 (6): 1257-1266], but without resection between ligatures. Simulated control rats (sham) were operated. Behavioral studies were initiated 48 hours after surgery, when signs of pain or discomfort were no longer evident. Pharmacological treatments (with peptide or vehicle) began 3 weeks after surgery. Palmitoil-SEQ ID NO: 16-NH _{2 was administered} at a dose of 5 mg / kg or vehicle (DMSO) intraperitoneally and activity was monitored up to 72 h after injection. The Hargreaves plantar test was used with conventional equipment (Ugo Basile, Italy) that automatically measured the latency response of the leg withdrawal to a radiant thermal stimulus. To avoid tissue injury in animals that do not respond, stimulation is terminated automatically after 32 s. The latency of the withdrawal of the leg was determined before and after drug or vehicle treatments in rats subjected to BDL and control with simulated operation.

For the scratch analysis, the rats were acclimatized for 30 min in a measuring cage, followed by video recording of the scratching behavior for 30 min or 1 h. Spontaneous scratching was quantified by counting the number of scratches in any region of the body performed by the front and rear legs. The data are presented in Figure 3 as mean ± sem with a minimum of six animals per group.

The results showed that Palmitoil-SEQ ID NO: 16-NH ₂ at 5 mg / kg significantly reduced thermal hyperalgesia and scratching behavior. This peptide activity lasted up to 48 h after administration.

EXAMPLE 33

Attenuation of cold hyperalgesia produced by intraplantar invention of Freund's complete adjuvant (CFA).

The in vivo anti-nociceptive effect of the compound was explored

Palmitoil-SEQ ID NO: 31 -NH ₂ evaluating the effect of cold hyperalgesia caused by plantar administration of CFA.

Wistar rats (200-300 g) were used for the study. An emulsion of CFA (oil / saline solution 1: 1, 0.5 mg / ml) was injected into the plantar surface (50 μΐ) [García-Martínez C. et al. (2006) J. Pain 7 (10): 735-746]. Palmitoil-SEQ ID NO: 31-NH ₂ (5 mg / kg) or vehicle (DMSO) was administered intraperitoneally 24 hours after CFA injection. Cold hyperalgesia was monitored 24 hours after CFA injection and up to 6 hours after administering treatments by monitoring the behavior of animals after the application of acetone in the homolateral leg [Knowlton WM et al. (201 1) PLoS ONE 6 (9): e25894]. The evaporative cooling test was performed as follows: the rats were acclimatized for 15 min in an elevated four-compartment chamber with a mesh floor. A syringe was filled with a piece of rubber tube attached to the walls with acetone and the plunger was squeezed so that It will form a small drop of acetone on the top of the tube. The syringe was raised to the rear leg of the rat from below, placing the drop of acetone on the leg. Four rats were tested at the same time with an inter-stimulation period of 4 min per rat, alternating the legs between the stimulations. The responses for subsequent quantification by a blind observer to the experimental conditions were videotaped. Behaviors were scored according to the magnitude of the response along the following scale: 0-no response, 1-brief elevation, sniffing, slap or startle; 2-jump, leg shake; 3-multiple lifts, leg licking; 4-jump, shake, lick or long leg lift; 5-leg protection. The scale was designed so that extreme values (0 and 5) were only produced a few times. Data are represented as the mean ± standard error with a minimum of six animals per group. Statistical significance was evaluated using the Student t test or paired data or independent data and was set at p <0.05 using the Graphpad Prism 5.0 software package.

The results showed that Palmitoil-SEQ ID NO: 31 -NH ₂ at 5 mg / kg significantly reduced cold hyperalgesia caused by CFA injection.

Homolateral Contralateral

Answer Answer

Vehicle 4 ± 1 1 ± 1

Palmitoil-SEQ ID NO: 31 -NH ₂ 2 ± 1 1 ± 1

Statistically significant in YES No

comparison with the vehicle (p <0.05)

Table 1 1

EXAMPLE 34

Attenuation of mechanical allodynia produced by intraplantar invention of Freund's complete adjuvant (CFA).

The in vivo anti-nociceptive effect of the Palmitoil-SEQ ID NO: 33-NH ₂ compound was explored by evaluating the effect on mechanical allodynia produced by plantar administration of CFA.

Wistar rats (200-300 g) were used for the study. An emulsion of CFA (oil / saline solution 1: 1, 0.5 mg / ml) was injected into the plantar surface (50 μΐ). Be administered Palmitoil-SEQ ID NO: 33-NH ₂ (5 mg / kg) or vehicle (DMSO) intraperitoneally 24 hours after CFA injection. Mechanical allodynia was followed up to 48 hours after administering the treatments using Von Frey filaments with the "up and down" method. The rats were placed on a raised wire mesh grid (6 x 6 mm ² openings) under plastic chambers. To quantify the mechanical sensitivity of the legs, filaments with different forces (in grams) were applied 10 times to the hind leg in an ascending order of strength. The frequency of withdrawal responses was monitored and represented as the percentage of response. The filament was applied for 1 to 2 seconds, with an interval between stimuli of 5 to 10 seconds [García-Martínez C. et al. (2006) J. Pain 7 (10): 735-746]. Data from the area under the curve (AUC) were calculated, and unilateral ANOVA was used followed by Dunnett's post hoc test as a statistical analysis. Statistical significance was set at p <0.05. The Graphpad Prism 5.0 software package was used for statistical analysis.

The results showed that Palmitoil-SEQ ID NO: 33-NH ₂ at 5 mg / kg significantly reduced the mechanical allodynia produced by CFA injection.

Homolateral Contralateral

Mechanical (AUC) Mechanical (AUC)

Vehicle 1681 ± 232 593 ± 129

Palmitoil-SEQ ID NO: 33-NH ₂ 651 ± 147 623 ± 14

Statistically significant in SI No comparison with the vehicle (p <0.05)

Table 12

Claims

Peptide selected from the group consisting of:

(iii) peptide comprising the sequence SEQ ID NO: 3 or a functionally equivalent variant, where the length of said peptide is equal to or less than 25 amino acids and where the arginine and glutamine of SEQ ID NO: 3 remain unchanged and where the peptide is not the sequence peptide SEQ ID NO: 4;

(iv) peptide comprising the sequence SEQ ID NO: 5 or a functionally equivalent variant, where the length of said peptide is equal to or less than 20 amino acids, and where the peptide is not the sequence peptide SEQ ID NO: 6;

(viii) peptide comprising the sequence SEQ ID NO: 10 or a functionally equivalent variant, wherein the length of said peptide is equal or less than 20 amino acids, and where the amino acid of the / V-terminal end of SEQ ID NO: 10 can only be isoleucine or leucine, and the valine of said sequence remains unchanged;

2. A peptide according to claim 1, which has a substituent at the V-terminus selected from the group consisting of H, a polymer derived from polyethylene glycol and R-CO-, wherein R is selected from the group consisting of C1-C24 alkyl radical substituted or unsubstituted alkenyl C ₂ -C _{4 February} substituted or unsubstituted alkynyl, C ₂ -C _{4 February} substituted or unsubstituted cycloalkyl C ₃ -C ₂₄ substituted or unsubstituted, cycloalkenyl C ₅ -C ₂₄ substituted or unsubstituted , substituted or unsubstituted C ₈ -C ₂₄ cycloalkynyl, C ₆ -C ₃ or substituted or unsubstituted aryl, substituted or unsubstituted C ₇ -C ₂₄ aralkyl, substituted or unsubstituted 3-10 ring heterocyclyl, and heteroarylalkyl substituted or unsubstituted from 2 to 24 carbon atoms and 1 to 3 atoms other than carbon and an alkyl chain of 1 to 6 carbon atoms.

3. Peptide according to claim 2, wherein the substituent is selected from the group consisting of H, a polymer derived from polyethylene glycol of molecular weight between 200 and 35,000 Daltons, acetyl, irec-butanoyl, prenyl, hexanoyl, 2-methylhexanoyl, cyclohexanecarboxyl, octanoyl, decanoyl, lauroyl, myristoyl, palmitoyl, stearoyl, oleoyl and linoleoyl.

4. Peptide according to any of claims 1 to 3, having a substituent at the C-terminus selected from the group consisting of -NR- | R _2, -OR 1, -SR-i, where R1 and _R2 are independently selected from the group consisting of H, a polymer derived from polyethylene glycol, CrC ₂₄ alkyl substituted or not substituted, substituted or unsubstituted C ₂ -C ₂ 4 alkenyl, substituted or unsubstituted C ₂ -C ₂ 4 alkynyl, substituted or unsubstituted C ₃ -C ₂₄ cycloalkyl, substituted or unsubstituted C ₅ -C ₂₄ cycloalkenyl, C-cycloalkynyl _8- C ₂₄ substituted or unsubstituted, C ₆ -C ₃ or substituted or unsubstituted aryl, substituted or unsubstituted C ₇ -C ₂₄ aralkyl, 3-10 substituted or unsubstituted heterocyclyl ring, and substituted or unsubstituted heteroarylalkyl substituted from 2 to 24 carbon atoms and 1 to 3 different carbon atoms where the alkyl chain is 1 to 6 carbon atoms, and where Ri and R ₂ can be linked by a carbon-carbon bond, saturated or unsaturated, forming a cycle with the nitrogen atom.

5. Peptide according to claim 4, wherein the substituent is selected from the group consisting of -NFR ₂ and -ORi, and Ri and R ₂ are selected from the group consisting of H, a polymer derived from polyethylene glycol of molecular weight between 200 and 35000 Daltons, methyl, ethyl, hexyl, dodecyl and hexadecyl.

6. Peptide according to any one of claims 1 to 5, wherein the peptide is selected from the group consisting of the sequence peptides SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 5, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 1 1, SEQ ID NO: 12, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29 and SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33 and SEQ ID NO: 34.

7. Method of preparing the peptide, its stereoisomers, mixtures thereof and / or its cosmetically or pharmaceutically acceptable salts according to any of claims 1 to 6, characterized in that it is carried out in solid phase or in solution or is a combination of the synthesis in solid phase and in solution.

8. Method of preparing the peptide, its stereoisomers, mixtures thereof and / or its cosmetically or pharmaceutically acceptable salts according to claim 7, characterized in that the protecting groups of the free amino groups are selected from the group consisting of acetate, benzoate, pivalate , carbamates, Boc, Fmoc, Troc, Teoc, Alloc, Trt, Mtt, Z, CbZ, CIZ, Dnp, Dde, ivDde and Adpoc, the protective groups of the free carboxyl groups are selected from the group consisting of esters of tBu, Bzl , cHx, All, Dmab, 2-phenylisopropyl, orio-nitrobenzyl, para-nitrobenzyl, para-methoxybenzyl, TMS, Fm and Trt, the chain Arginine side is protected with a protective group selected from the group consisting of Tos, Mtr, Alloc, nitro, Pbf and Pmc, the lysine side chain is protected with a protective group selected from the group consisting of CIZ, Z, 4-nitroZ, Fmoc, Boc, Ac, Tos, Dde, ivDde, Dnp, Mtt and Alloc, the side chains of aspartic acid and glutamic acid are protected with a protective group selected from the group consisting of Trt, Bzl, cHx, tBu and All, the chain Tyrosine side is protected with a protective group selected from the group consisting of 2-BrZ, Boc, All, 2,6-diCIZ, Bzl and tBu, the methionine side chain is used protected with the sulfoxide group or is used unprotected, the histidine side chain is protected with a protective group selected from the group consisting of Tos, Dnp, Me, Boc, Bom, Bzl, Fmoc, Mts, Trt and Mtt, the tryptophan side chain is protected with a protective group selected from the group formed by For, Boc and Mts or is used without protection, the lat chain Asparagine and glutamine is protected with a protective group selected from the group consisting of Trt, Mtt and Xan or is used without protection, and the threonine and serine side chain is protected with a protective group selected from the group consisting of tBu, Bzl, Trt and Ac.

9. Cosmetic or pharmaceutical composition comprising a cosmetic or pharmaceutically effective amount of at least one peptide according to any one of claims 1 to 6, and at least one cosmetic or pharmaceutically acceptable excipient or adjuvant.

10. Composition according to claim 9, wherein said peptide, its stereoisomers, mixtures thereof and / or its cosmetically or pharmaceutically acceptable salts, is at a concentration between 0.000001% and 20% by weight, with respect to to the total weight of the composition.

eleven . Composition according to claim 10, wherein said peptide, its stereoisomers, mixtures thereof and / or its cosmetically or pharmaceutically acceptable salts, is at a concentration between 0.0001% and 5% by weight, based on weight Total composition.

12. Cosmetic or pharmaceutical composition according to any of claims 9 to 1 1, wherein the peptide, its stereoisomers, mixtures thereof, or its cosmetically or pharmaceutically acceptable salts, is incorporated into a carrier or a sustained release system selected from the group consisting of liposomes, mixed liposomes, oleosomes, niosomes, ethosomes, miliparticles, microparticles, nanoparticles, solid lipid nanoparticles, lipid supports nanostructured, sponges, cyclodextrins, vesicles, micelles, mixed surfactant micelles, mixed phospholipid-surfactant micelles, microspheres, microspheres, nanospheres, lipospheres, microcapsules, microcapsules, nanocapsules, microemulsions and nanoemulsions

13. Composition according to any of claims 9 to 12, wherein the peptide, its stereoisomers, mixtures thereof and / or its cosmetically or pharmaceutically acceptable salts, is adsorbed on a solid organic polymer or solid mineral support selected from the group consisting of talc, bentonite, silica, starch and maltodextrin.

14. Composition according to any of claims 9 to 13, wherein said composition is presented in a formulation selected from the group consisting of creams, multiple emulsions, anhydrous compositions, aqueous dispersions, oils, milks, balms, foams, lotions, gels, cream gels , hydroalcoholic solutions, hydro-glycol solutions, hydrogels, liniments, serums, soaps, shampoos, conditioners, serums, ointments, mousses, ointments, powders, bars, pencils, vaporizers, aerosols, capsules, gelatin capsules, soft capsules, hard capsules, tablets , sugar-coated tablets, tablets, pills, granulated forms, chewing gums, solutions, suspensions, emulsions, syrups, elixirs, polysaccharide films, jellies and jellies.

15. Composition according to any of claims 9 to 14, wherein said composition is incorporated into a product selected from the group consisting of make-up bottoms, make-up lotions, cleansing milks, dark circles, eye shadow, lipstick, lip gloss , lip protectors, lip gloss and powders.

16. Composition according to any of claims 9 to 15, characterized in that the peptide, its stereoisomers, mixtures thereof and / or its cosmetically or pharmaceutically acceptable salts, is incorporated into a tissue, a non-woven fabric or a product sanitary.

17. Composition according to claim 16, wherein said fabric, non-woven fabric or sanitary product is selected from the group consisting of bandages, gauze, shirts, socks, socks, underwear, girdles, gloves, diapers, compresses, dressings, bedspreads, wipes, adhesive patches, non-adhesive patches, occlusive patches, microelectric patches and facial masks.

18. Composition according to any of claims 9 to 17, characterized in that said composition additionally comprises a cosmetic or pharmaceutically effective amount of at least one adjuvant selected from the group consisting of other anti-inflammatory and / or analgesic agents, other anti-pruritus agents, soothing agents, agents anesthetics, inhibitors of aggregation of acetylcholine receptors, inhibitors of muscle contraction, anticholinergic agents, elastase inhibitors, inhibitors of matrix metalloproteases, agents that stimulate or inhibit melanin synthesis, bleaching or depigmenting agents, propigmenting agents, self-tanning agents, anti-aging agents, NO-synthase inhibitors, 5-reductase inhibitors, lysyl- and / or prolyl-hydroxylase inhibitors, antioxidant agents, free radical scavengers and / or atmospheric anti-pollution ica, carbonyl reactive species capture agents, anti-glycation agents, antihistamine agents, antiviral agents, antiparasitic agents, emulsifying agents, emollients, organic solvents, liquid propellants, skin conditioners, humectants, moisture-retaining substances, alpha hydroxy acids, betahydroxy acids, moisturizers , hydrolytic epidermal enzymes, vitamins, amino acids, proteins, pigments or dyes, dyes, biopolymers, gelling polymers, thickening agents, surfactants, softening agents, emulsifiers, binding agents, preservatives, wrinkle agents, agents capable of reducing or treating the bags under the eyes, exfoliating agents, antimicrobial agents, antifungal agents, fungistatic agents, bactericidal agents, bacteriostatic agents, agents that stimulate the synthesis of dermal or epidermal macromolecules and / or capable of inhibiting or preventing their degradation, stimulating agents of collagen synthesis, elastin synthesis stimulating agents, decorin synthesis stimulating agents, laminin synthesis stimulating agents, defensin synthesis stimulating agents, aquaporin synthesis stimulating agents, stimulating agents hyaluronic acid synthesis, fibronectin synthesis stimulating agents, sirtuin synthesis stimulating agents, heat shock protein synthesis stimulating agents, lipid synthesis and corneal stratum synthesis stimulating agents, ceramides, fatty acids , collagen degradation inhibitors, elastin degradation inhibitors, serine protease inhibitors such as cathepsin G, agents fibroblast proliferation stimulators, keratinocyte proliferation stimulating agents, adipocyte proliferation stimulating agents, melanocyte proliferation stimulating agents, keratinocyte differentiation stimulating agents, adipocyte differentiation stimulating agents, adipocyte differentiating agents acetylcholinesterase, dermarelaxing agents, glycosaminoglycan synthesis stimulating agents, antihyperkeratosis agents, comedolytic agents, antipsoriasis agents, DNA repair agents, DNA protective agents, stabilizers, agents for the treatment and / or care of sensitive skin, firming agents, anti-stretch agents, astringent agents, sebum production regulating agents, lipolytic agents or lipolysis stimulants, anti-cellulite agents, antiperspirant agents, healing agents, healing agents, healing agents ion, reepithelializing agents, reepithelializing agents, cytokine growth factors, agents acting on capillary circulation and / or microcirculation, angiogenesis stimulating agents, vascular permeability inhibiting agents, venotonic agents, agents acting on the metabolism of cells, agents intended to improve the dermis-epidermis junction, hair growth inducing agents, hair growth inhibiting or retarding agents, hair loss retarding agents, preservatives, perfumes, chelating agents, plant extracts, essential oils, marine extracts, agents from a biofermentation process, mineral salts, cell extracts, sunscreens and photoprotective agents of an organic or mineral nature, active against ultraviolet rays A and / or B, or mixtures thereof.

19. Composition according to claim 18, wherein said adjuvant is of synthetic origin or is a plant extract, or comes from a biotechnological process, or comes from a combination of a synthetic procedure and a biotechnological process.

20. Composition according to any of claims 18 to 19, wherein the anti-wrinkle agent and / or anti-aging agent is selected from the group consisting of extracts of Vitis vinifera, Rosa canina, Turmeric longa, Iris pallida, Theobroma cacao, Ginkgo biloba, Leontopodium Alpinum and Dunaliella saline, Acetyl Hexapeptide-8, Acetyl Heptapeptide-4, Acetyl Octapeptide-3, Pentapeptide-18, Acetyl Hexapeptide-30, Hydrolyzed Wheat Protein Blend, Protein Soy Hydrolyzed and Tripeptide-1, Diaminopropionoyl Tripeptide-33, Tripeptide-10 Citrulline, the mixture of Pseudoalteromone Ferment Extract, Hydrolyzed Wheat Protein, Hydrolyzed Soy Protein, Tripeptide-10 Citrulline and Tripeptide-1, Acetyl Tetrapeptide-5, Acetyl Tripeptide-30 Citrulline, Acetylaginyltriptofil Diphenylglycine, Acetyl Tetrapeptide-22, Dimethylmethoxy Cromanol, Dimethylmethoxy Cromanil Palmitate, Pseudoalteromonas Ferment Extract, Lysine HCI Blend, Lecithin and Tryptin-9, Citrine Lysine-9 10 Citrulline, other calcium channel antagonists, alverin, manganese or magnesium salts, magnesium gluconate, secondary or tertiary amines, retinol and its derivatives, idebenone and its derivatives, Coenzyme Q10 and its derivatives, boswellic acid and its derivatives, GHK and its derivatives, carnosine and its derivatives, DNA repair enzymes, photoliase, T4 type V endonuclease and c channel agonists loruro

Composition according to any one of claims 18 to 19, wherein the anti-inflammatory and / or analgesic agent is selected from the group consisting of madecasoside, equinacin, amaranth seed oil, sandalwood wood oil, peach leaf extract, Aloe vera extracts Arnica montana, Artemisia vulgaris, Asarum máximum, Calendula officinalis, Capsicum, Centipeda cunninghamii, Chamomilla recutita, Crinum asiaticum, Hamamelis virginiana, Harpagophytum procumbens, Hypericum perforatum, Lilium candidum, Malva sylvestrusjous, Melavesumusus, Melaves Origus, Prune , Rosmarinus officialis, Salix alba, Silybum marianum, Tanacetum parthenium, Thymus vulgaris, Uncaria guianensis and Vaccinum myrtillus, mometasone furoate and prednisolone, non-steroidal anti-inflammatories including cyclooxygenase or lipoxygenase inhibitors, benzyl amine, acidic acid , derivatives of glicirricinat or, obisabolol, azulene and the like, sericoside, ruscogenin, escina, scoline, rutin and the like, hydrocortisone, clobetasol, dexamethasone, prednisone, paracetamol / acetaminophen, amoxiprin, benorilate, choline salicylate, diflunisal, phathylamine, salicylate, salicylate, salicylate, salicylate, salicylate, salicylate magnesium, olsalacina, sulfasalacina, salsalate, diclofenac, aceclofenac, acemetacina, bromfenaco, etodolaco, zolmepiraco, indometacina, oxametacina, proglumetacina, sulindaco, tolmetina, ibuprofeno, dexibuprofeno, carprofeno, fenbufenopenopnophenophenophenophenophenophene, kebufenophenophenophenophenophenopheneprimenephene loxoprofen, naproxen, miroprofen, oxaprozin, pranoprofen, thiaprofenic acid, suprofen, mefenamic acid, meclofenamate, meclofenamic acid, flufenamic acid, tolfenamic acid, nabumetone, phenylbutazone, azapropazone, clofezone, kebuzone, metamizole, mofebutazone, oxyphenbutazone, phenazone, sulfinpyrazone, piroxicam, lornoxicam, meloxicam, tenoxicam, celecoxib, etoricoxib, lumiracoxib, parecoxib, rofecoxib, valdecoxib, nimesulide, naproxcinod, flufenisal, fluprocuazone or licofelone; morphine, codeine, oxycodone, hydrocodone, diamorphine, pethidine, tramadol, brupenorphine, benzocaine, lidocaine, chloroprocaine, tetracaine, procaine, anticonvulsants, tricyclic antidepressants, amitriptyline, carbamazepine, gabapentin, pregabalimine, pantenolotodium, panthenol, panthenol cyclopyrox olamine, nordihydroguaarytic acid, coenzyme Q10 and alkyl glycerin ethers

22. Composition according to any of claims 18 to 19, wherein the antipruritic agent is selected from the group consisting of the extracts of Abelmoschus esculentus, Actaea alba, Aglaia odorata, Alkanna tinctoria, Althaea officinalis, Altingia excelsa, Andropogon virginicus, Aralia nudicaulis, Aralia racemosa, Mexican Argemone, Barleria prionitis, Camelia sinensis, Caesalpinia digyna, Campsis grandiflora, Carissa congesta, Carthamus oxyacantha, Cassia tora, Chrysanthemum indicum, Cimicifuga racemosa, Cinnamomum camphora, Clematis vitalba, Cuscurosma pereginalisa virginia Jatropha multifida, Lavandula officinalis, Lavandula latifolia, Liquidambar orientalis, Lithospermum officinale, Madhuca longifolia, Martynia annua, Medicago sativa, Michelia champaca, Mikania glomerata, Mimosa púdica, Oryza sativa, Phaseolus vulgaris, Phyllanthus urinaria, Phyllanthus virinariara, Phyllanthus urinariara, Phyllanthus virinariara, Phyllanthus virinariara, Phyllanthus virinariara, Phyllanthus virinariara, Phyllanthus urinariara, Phyllanthus urinariara, Phyllanthus urinariara, Phyllanthus urinariara, Phyllanthus urinariara, Phyllanthus urinariara, Phyllanthus virinariara Quercus ilex, Rauvolfia caffra Ricinus communis, Rubus idaeus, Sagittaria sagittifolia, Sandoricum koetjape, Sapindus mukorossi, Schleichera oily, Sesbania grandiflora, Spondias dulcís, Tilia sp. / pyrilamine, antazoline, diphenhydramine, carbinoxamine, doxylamine, clemastine, dimenhydrinate, phenyramine, chlorphenamine / chlorpheniramine, dexchlorpheniramine, bronpheniramine, triprolidine, cyclicine, chlorocycline, hydroxyzine, medicine, cetirizine, levocetzetzethazetzethazetzethazethazethazine , acrivastine, astemizola, cetirizine, loratadine, desloratadine, mizolastine, terfenadine, fexofenadine, fexofenadine, azelastine, levocabastine, olopatadine, corticosteroids, cortisone, hydrocortisone, dexamethasone and prednisone.

23. Composition according to any of claims 9 to 22, which is administered topically, enterally or parenterally.

24. Composition according to claim 23, which is administered topically, transdermally, orally, nasally, or inhalationally, or by intramuscular, intravenous, intraperitoneal or subcutaneous injection.

25. Composition according to any of claims 23 to 24, wherein the topical or transdermal administration is performed by iontophoresis, sonophoresis, electroporation, mechanical pressure, osmotic pressure gradient, occlusive cure, microinjections, needleless injections by pressure, microelectric patches or any combination of them.

26. At least one peptide selected from the group consisting of:

(¡) Peptide comprising the sequence SEQ ID NO: 1 or a functionally equivalent variant, where the length of said peptide is equal to or less than 25 amino acids and where the asparagine of the sequence SEQ ID NO: 1 remains unchanged;

(iii) peptide comprising the sequence SEQ ID NO: 3 or a functionally equivalent variant, where the length of said peptide is equal to or less than 25 amino acids and where the arginine and glutamine of SEQ ID NO: 3 are maintained;

(¡V) peptide comprising the sequence SEQ ID NO: 5 or a functionally equivalent variant, wherein the length of said peptide is equal to or less than 20 amino acids;

(v¡) peptide comprising the sequence SEQ ID NO: 8 or a functionally equivalent variant, wherein the length of said peptide is equal or less than 20 amino acids, and where the valine and / or tryptophan of SEQ ID NO: 8 remain unchanged;

their stereoisomers, mixtures thereof and / or their cosmetically or pharmaceutically acceptable salts for use in the treatment and / or prevention of pain, inflammation, pruritus, diseases and / or disorders of the respiratory tract and / or diseases and / or disorders associated with calcium imbalances.

At least one peptide selected from the group consisting of:

(iii) peptide comprising the sequence SEQ ID NO: 3 or a functionally equivalent variant, wherein the length of said peptide is equal or less than 25 amino acids and where the arginine and glutamine of SEQ ID NO: 3 are maintained;

its stereoisomers, mixtures thereof and / or their cosmetically or pharmaceutically acceptable salts for use in the treatment and / or care of the skin, mucous membranes and / or nails.

At least one peptide, selected from the group consisting of:

(i) peptide comprising the sequence SEQ ID NO: 1 or a functionally equivalent variant, where the length of said peptide is equal to or less than 25 amino acids and where asparagine remains unchanged;

At least one peptide selected from the group consisting of:

(i) peptide comprising the sequence SEQ ID NO: 9 or a functionally equivalent variant, where the length of said peptide is equal to or less than 20 amino acids, and where the isoleucine of SEQ ID NO: 9 remains unchanged; (ii) peptide comprising the sequence SEQ ID NO: 10 or a functionally equivalent variant, where the length of said peptide is equal to or less than 20 amino acids, and where the amino acid of the V-terminal / end of SEQ ID NO: 10 it can only be isoleucine or leucine, and the valine of said sequence remains unchanged;

its stereoisomers, mixtures thereof and / or their cosmetically or pharmaceutically acceptable salts for use in the inhibition of the TRPA1 receptor.

31. At least one peptide selected from the group consisting of:

SEQ ID NO: 8 remain unchanged;

32. At least one peptide for use according to claim 31, wherein the cancer is prostate cancer and / or pancreatic cancer.

33. At least one peptide for use according to any of claims 26 to 32, wherein the peptide has a substituent at the selected / V-terminal end the group consisting of H, a polymer polyethylene glycol derivative R-CO-, wherein R is selected from the group consisting radical C1-C24 substituted or unsubstituted alkenyl, C ₂ -C _{4 February} substituted or unsubstituted alkynyl , C ₂ -C ₂ 4 substituted or unsubstituted, C ₃ -C ₂₄ substituted or unsubstituted cycloalkyl, substituted or unsubstituted C ₅ -C ₂₄ cycloalkenyl, C ₈ -C ₂₄ substituted or unsubstituted cycloalkynyl, C ₆ -C ₃ aryl or substituted or unsubstituted, substituted or unsubstituted C ₇ -C ₂₄ aralkyl, 3-10 substituted or unsubstituted heterocyclyl ring, and substituted or unsubstituted heteroarylalkyl of 2 to 24 carbon atoms and 1 to 3 carbon atoms and an alkyl chain of 1 to 6 carbon atoms.

34. At least one peptide for use according to claim 33, wherein the substituent is selected from the group consisting of H, a polymer derived from polyethylene glycol of molecular weight between 200 and 35,000 Daltons, acetyl, irec-butanoyl, prenyl, hexanoyl, 2-methylhexanoyl, cyclohexanecarboxyl, octanoyl, decanoyl, lauroyl, myristoyl, palmitoyl, stearoyl, oleoyl and linoleoyl.

35. At least one peptide for use according to any of claims 26 to 34, wherein the peptide has a substituent at the C-terminus selected from the group consisting of -NR, -OR1, -SR1, where R1 and _R2 are independently selected from the group consisting of H, a polymer derived from polyethylene glycol, alkyl CrC ₂₄ substituted or unsubstituted alkyl , C ₂ -C ₂₄ substituted or unsubstituted alkenyl, C ₂ -C ₂₄ substituted or unsubstituted cycloalkyl C ₃ -C ₂₄ substituted or unsubstituted, C ₅ -C ₂₄ substituted or unsubstituted cycloalkenyl, C ₈ -C ₂₄ substituted or unsubstituted cycloalkynyl, C ₆ -C ₃ aryl or substituted or unsubstituted, C ₇ -C ₂₄ substituted or unsubstituted aralkyl , 3-10 substituted or unsubstituted ring heterocyclyl, and substituted or unsubstituted heteroarylalkyl of 2 to 24 carbon atoms and 1 to 3 different carbon atoms where the alkyl chain is 1 to 6 carbon atoms, and where R1 and R ₂ can be joined m by means of a carbon-carbon bond, saturated or unsaturated, forming a cycle with the nitrogen atom.

36. At least one peptide for use according to claim 35, wherein the substituent is selected from the group consisting of -NR ^ and -OR1, and R1 and R ₂ are selected from the group consisting of H, a polymer derived from polyethylene glycol by weight molecular between 200 and 35000 Daltons, methyl, ethyl, hexyl, dodecyl and hexadecyl.

37. At least one peptide for use according to claim 26 for use in the treatment and / or prevention of pain, inflammation, pruritus, diseases and / or disorders of the respiratory tract and / or diseases and / or disorders associated with calcium imbalances that are a consequence or concur with epithelial, gastrointestinal, cardiovascular system, urinary tract, disease, endocrine system, brain, reproductive system diseases , of the respiratory tract and / or cancer.

38. At least one peptide for use according to claim 37, wherein the pain is selected from the group consisting of acute pain, chronic pain, nociceptive pain, neuropathic pain, inflammatory pain, visceral pain, abdominal pain, digestive system pain, pain of the respiratory system, urogenital system pain, endocrine system pain, heart pain, pancreatic pain, liver pain, pain due to gallstones, cholestasis, intestinal pain, stomach pain, pain due to duodenal ulcer, pain due to esophagitis, pain due to gastroesophageal reflux, spleen pain, blood vessel pain, pain due to thalamic syndrome, irritable bowel syndrome, pain associated with Crohn's disease, diverticulitis, gastrointestinal mucositis, headache, tension headache, pain Headache associated with sinusitis, migraine, eye pain, dry eye syndrome, post-operative pain, post-operative pain due to incisions It is surgical, post-operative pain due to the insertion of bone implants, post-operative pain due to bone replacement, post-operative pain due to infections, post-operative pain due to limb amputations, pain due to bone fractures, pain due to cancer, pain due to bone cancer, pain associated with benign bone tumors, pain associated with osteoid osteomas, pain associated with osteoblastomas, pain due to cancer treatment, pain due to chemotherapy, pain due to emesis pain due to emesis resulting from chemotherapy treatment, musculoskeletal pain, spastic muscle pain, fibromyalgia, complex regional pain syndrome, psychogenic pain, nerve pain, pain due to demyelinating diseases, neck pain associated with cervical dystonia, back pain , low back pain, sciatica, neurogenic inflammation, neuritis, causalgia, touch sensitivity, cold sensitivity, heat sensitivity, skin irritation, post-depilation skin irritation, post-shave skin irritation, psoriasis, sensitive skin, dermatitis, atopic dermatitis, contact dermatitis, diaper dermatitis, eczema, burns, sunburn, arthritis, rheumatoid arthritis, osteoarthritis , psoriatic arthritis, uveitis, pain due to nerve injuries, neuralgia, post-herpetic neuralgia, neuropathies, peripheral neuropathies, pain phantom, allodynia, hyperalgesia, cold hyperalgesia, pain due to carpal tunnel syndrome, burning pain, Grierson-Gopalan syndrome, burning mouth syndrome, paraesthesia, Fabry disease, facial pain, trigeminal neuralgia, neuropathic pain due to diabetes , neuropathic pain due to AIDS, orofacial pain, dental pain, tooth extraction pain, wisdom tooth extraction pain, cold dental sensitivity, heat dental sensitivity, oral mucositis, temporomandibular joint pain, associated pain tattooing or tattoo removal processes, pain due to bunions, testicular pain, myofascial pain, urinary bladder pain, urinary tract pain, cystitis, pain due to kidney stones, renal cramps, vulvar pain, vaginal pain, post-pain childbirth, menstrual pain, scrotal pain, perineal pain, pelvic pain or hypersensitivity, pain or skin irritation after surgery, t After treatment with pulsed light therapy, after treatment with monochromatic or laser pulsed light therapy, after treatment with chemical descaling agents or after overexposure to aggressive external agents and pain due to chronic alcoholism.

39. At least one peptide for use according to claim 37, wherein the inflammation is selected from the group consisting of neurogenic inflammation, joint inflammation, tendon inflammation, muscle inflammation, sepsis, vascular inflammation, respiratory inflammation, chronic obstructive pulmonary disease, asthma, otitis, intestinal inflammation, pancreatitis, hepatitis, conditions related to chronic inflammation, with acute inflammation, nephritis, systemic lupus erythematosus, inflammatory bowel disease, Crohn's disease, rheumatoid arthritis, osteoarthritis, glomerulonephritis, neuritis, inflammation of the nervous tissue, sclerosis multiple, immune system disorders, Sjógren's syndrome, rhinitis, atherosclerosis, myocarditis, pericarditis, vasculitis, psoriasis, sensitive skin, dermatitis, atopic dermatitis, contact dermatitis, diaper dermatitis, eczema, rosacea, burns, sunburn, vulvodynia, diseases inflammatory eyes and sarcoidosis.

40. At least one peptide for use according to claim 37, wherein the pruritus is an associated pruritus diseases and / or epithelial disorders selected from the group consisting of dermatitis, atopic dermatitis, photodermatosis, eczema, sensitive skin, psoriasis, dandruff, seborrhea, athlete's foot, sunburn, xerosis and dry skin, or pruritus associated with dialysis, pregnancy, menopause, infection of acquired immunodeficiency virus, chickenpox, herpes, malignant neoplasms, Hodgkin's disease, leukemia, myeloma, lymphoma, solid tumors, lung cancer, liver diseases, jaundice, cholestasis, liver failure, cirrhosis, polycythemia, hypereosinophilic syndrome, essential thrombocythemia, myelodysplastic syndrome, iron deficiency anemia, systemic lupus erythematosus , endocrine diseases, thyroid diseases, parathyroid diseases, diabetes mellitus, kidney diseases, uremia, parasitic infections, scabies, lice, intestinal worms, allergic reactions, drug allergies, food allergies, chemical allergies, exposure to poisonous plants, exposure to insect bites, chemotherapy, stress and anxiety.

41. At least one peptide for use according to claim 37, wherein the disorders and / or diseases of the respiratory tract are selected from the group consisting of obstructive diseases such as chronic obstructive pulmonary disease, emphysema, chronic bronchitis, asthma, asthma caused by industrial irritants, cystic fibrosis, bronchiectasis, bronchiolitis, allergic bronchopulmonary aspergillosis, or tuberculosis; Restrictive pulmonary diseases such as asbestosis, radiation-caused fibrosis, extrinsic allergic alveolitis or insensitivity pneumonitis, childhood respiratory distress syndrome, idiopathic pulmonary fibrosis, sarcoidosis, idiopathic interstitial pneumonia, eosinophilic pneumonia, lymphangioleiomyomatosis, Langerhave alveolar and pulmonary cell histiocytosis pulmonary; respiratory tract infections including common cold, sinusitis, tonsillitis, pharyngitis, laryngitis or pneumonia; Respiratory malignant tumors such as small cell lung cancer, non-small cell lung cancer, adenocarcinoma, squamous cell carcinoma, undifferentiated large cell carcinoma, carcinoid, mesothelioma, metastatic lung cancer, germ cell metastatic cancer, benign respiratory tumors as pulmonary hamartoma; congenital malformations such as bronchopulmonary sequestration and cystic adenomatoid congenital malformation; diseases of the pleural cavity such as empyema and mesothelioma; pulmonary vascular diseases such as embolism, pulmonary thromboembolism, gaseous or iatrogenic embolism, pulmonary arterial hypertension, pulmonary edema, pulmonary hemorrhage, inflammation and damage to the capillaries in the lungs resulting in blood dripping into the alveoli; disorders that affect the mechanics of breathing such as obstructive sleep apnea, central sleep apnea, amyotrophic lateral sclerosis, Guillain-Barré syndrome and myasthenia gravis; shortness of breath or breathlessness, cough, cough with blood or hemoptysis, chest pain such as pleuritic chest pain, noisy breathing, wheezing and cyanosis.

42. At least one peptide for use according to claim 37, wherein the diseases and / or disorders associated with calcium imbalance are selected from the group consisting of vitamin D deficiency, rickets, osteomalacia, growth retardation, osteoporosis, post osteoporosis - menopausal, hypercalciuria, hypocalciuria, hypercalcemia, hypocalcemia and parathyroid hormone related disorders.

43. At least one peptide for use according to claim 37, wherein the diseases and / or epithelial disorders are selected from the group consisting of touch sensitivity, cold sensitivity, heat sensitivity, skin irritation, post-depilation skin irritation, irritation post-shave skin, dermatitis, atopic dermatitis, allergic contact dermatitis, diaper dermatitis, photodermatosis, psoriasis, rosacea, eczema, burns, sunburn, sensitive skin, xerosis and dry skin.

44. At least one peptide for use according to claim 37, wherein the gastrointestinal diseases are selected from the group consisting of inflammatory bowel disease, intestinal colic, Crohn's disease, pancreatitis, hepatitis, gastroesophageal reflux disease, duodenal ulcer, esophagitis, colitis and ulcerative colitis.