CN103159831B - A kind of pentapeptide, polypeptide, Cyclopeptide derivatives, compound and medicine thereof and application - Google Patents

Abstract

The invention discloses a pentapeptide, a polypeptide with the pentapeptide as an active center, a cyclic peptide derivative and a compound, an immunosuppressive drug with the pentapeptide as an active center, and the application thereof in the immunosuppressive drug. The pentapeptide TIPP (thymic?immunosuppressive?pentapeptide) of the present invention is derived from LMW-TISE-c (low molecular weight bovine thymus immunosuppressive extract), which is as SEQ? ID? The amino acid sequence shown in NO.1: Ala-Glu-Trp-Cys-Pro. The present invention is the first in many years to obtain a structurally defined component from an immunosuppressive component of the thymus. The pentapeptide is derived from thymus immunosuppressive extract (TISE), and the invention can be used to prepare immunosuppressive drugs.

Description

Pentapeptide, polypeptide, cyclic peptide derivative, compound and its medicine and application

technical field

The invention relates to a pentapeptide, a polypeptide with the active center, a cyclic peptide derivative and a compound, an immunosuppressive drug with the active center, and the application thereof in the immunosuppressive drug.

Background technique

The thymus is an important central immune organ in mammals. In addition to providing a cellular microenvironment required for T cell development, the thymus also produces a variety of polypeptide hormones, which affect the differentiation and maturation of T cells, and also regulate the function of mature T cells, which play an important role in the immune function of the body. significance. At present, the extracts or factors in the thymus that enhance the immune ability of the body have been deeply understood and studied at home and abroad, such as thymosin and thymopentin, but there are few reports on the factors that suppress the immune function in the thymus.

In 1960, Bullough and Laurence obtained an inhibitor of epithelial cell division from epithelial cells, and proposed the concept of Chalone. Statins are a class of endogenous cytostatic factors. Since the 1970s, people have successively extracted a statin-like substance that inhibits lymphocyte division from bovine, pig and human embryonic thymus, and studies have shown that it has immunosuppressive activity and has no cytotoxicity. Abroad studies of thymus-derived substances with immunosuppressive function mainly refer to statin-like substances. Since the statin-like substances extracted from the thymus are all unknown mixtures, the researchers studied their components and properties. Houck et al. have isolated an immunosuppressant with a molecular weight of 30kD to 50kD, which contains nucleic acid and is heat-sensitive. Later, they hydrolyzed it with ribonuclease and ultra-filtered it to recover components with immunosuppressive activity and speculated that statin was A positively charged glycopeptide with a molecular weight of around 5kD. Kiger et al. in France prepared lymphocyte inhibitory factor through gel filtration and ion exchange chromatography. After analysis, it was speculated that it may be a basic polypeptide with thermostability and binding to nucleotides. Allen et al. believe that the biologically active substance of lymphocyte inhibitory factor is spermine, which has a molecular weight of only 202D. In the extract, it combines with a tissue-specific substance to form a tight spermine complex, which shows specific immunosuppressive activity. Rijke et al. found that lymphocyte inhibitory factor is a complex of spermine and protein. In the lymphocyte transformation inhibition test, it is spermine that really inhibits, but in the study using spermine as a control, it was found that it could not inhibit lymphocytes. Cell Transformation. Patt et al. proved that the lymphocyte transformation inhibitory factor is a peptide with a molecular weight of 500D to 600D, hydrophobic, acidic, and containing sulfhydryl groups. Blazsek proved that the inhibitor of lymphocyte transformation is the component of pI5.9. Heating, adding protein denaturant (4mol/L deionized urea) or protease can destroy its activity, but digestion with ribonuclease can destroy its activity. No effect. Although the properties of thymus-derived immunosuppressants were studied by early researchers, no recent studies have been reported on them, and no structurally defined single compounds have been identified from them.

Contents of the invention

The purpose of the present invention is to overcome the deficiencies of the above-mentioned prior art, to provide a pentapeptide, a polypeptide with it as an active center, a cyclic peptide derivative and a compound, and an immunosuppressive drug with it as an active center, and its use in immune Inhibiting drug use.

To achieve the above object, the present invention adopts the following technical solutions:

A thymic immunosuppressive pentapeptide TIPP (thymicimmunosuppressivepentapeptide), derived from LMW-TISE-c (low molecular weight bovine thymus immunosuppressive extract), which is the amino acid sequence shown in SEQ ID NO.1:

Ala-Glu-Trp-Cys-Pro.

A polypeptide obtained by adding one or more of L-amino acid, D-amino acid, hydroxyl amino acid, methylated amino acid or heterocyclic amino acid from the N-terminal or C-terminal of the pentapeptide as the active center.

The heterocyclic amino acid is tryptophan, histidine or proline.

A cyclic peptide derivative obtained by linking the N-terminal and C-terminal of the pentapeptide to form a ring.

The compound obtained by acetylation, formylation, alkylation at the N-terminal of the pentapeptide, or aminoacylation or esterification at the C-terminus has greatly improved the biological activity, half-life, stability, etc. of the pentapeptide. improve.

Said alkylation is methylation, ethylation, propylation or butylation.

The esterification is an esterification reaction with methanol, ethanol, butanol or hexanol.

An immunosuppressive drug, the active ingredient of which includes the application of the above-mentioned pentapeptide, polypeptide, cyclic peptide derivatives or compounds in the preparation of immunosuppressive drugs.

Application of the above-mentioned pentapeptide, polypeptide, cyclic peptide derivative or compound in the preparation of immunosuppressive drugs.

The pentapeptide of the present invention can be obtained by known methods in the prior art. It can be chemically synthesized with an automatic peptide synthesizer, and the short peptide sequence can be deduced into a nucleotide sequence, and then cloned into an expression vector for biosynthesis.

The invention provides an immunosuppressive drug, the active ingredient of which includes the pentapeptide, a polypeptide with the pentapeptide as an active center, a cyclic peptide derivative and a compound. The above immunosuppressive drugs may also contain one or more pharmaceutically acceptable carriers. The carrier includes conventional diluents, excipients, fillers, binders, wetting agents, disintegrating agents, absorption promoters, surfactants, adsorption carriers, lubricants, etc. in the pharmaceutical field, and fragrances can also be added if necessary agents, sweeteners, etc. The immunosuppressive drug of the present invention can be made into various forms such as injection, powder injection, inhalation, tablet, powder, capsule, oral liquid and the like. The above-mentioned medicines in various dosage forms can be prepared according to conventional methods in the field of pharmacy.

The invention also provides the application of the pentapeptide, the polypeptide with the pentapeptide as the active center, the cyclic peptide derivative and the compound in the preparation of immunosuppressive drugs.

In particular, the application of the pentapeptide in the preparation of medicines for autoimmune diseases, organ transplantation, allergic diseases and inflammatory diseases.

Shandong Medical University (now Shandong University) School of Pharmacy conducted research on the development of thymosin in the mid-1980s and found that thymus immunosuppressive drugs prepared by acidic extraction mainly had immune-promoting activity, while thymus prepared by alkaline extraction The preparation is mainly immunosuppressive activity. Because the preparation method is different from the reported thymus-derived immunosuppressive drugs, the applicant named the extract prepared by the alkaline extraction method thymic immune suppressive extract (thymicimmunosuppressiveextract, TISE). Through the study of the biological activity and pharmacological effects of TISE and the similarities and differences of TISE activities derived from different animal thymus, it was found that TISE has inhibitory effects on cellular immunity and humoral immunity, as well as non-specific immune function, and can effectively inhibit skin transplantation. It also has the effect of resisting type I allergy and type III allergy, and the activity of TISE has no species specificity. This suggested the applicant's possibility of TISE as a new type of immunosuppressive drug.

The beneficial effects of the present invention are:

In order to reduce the possibility of allergic reactions caused by the use of TISE derived from xenogeneic sources in humans, TISE (TISE-c) derived from calf thymus was prepared into a low-molecular-weight TISE-c with a smaller molecular weight and stronger biological activity by using ultrafiltration technology. (LowMolecularWeightTISE-c, LMW-TISE-c). On this basis, micrococcal nuclease was used to degrade LMW-TISE-c and RP-HPLC separation, combined with acid hydrolysis, finally purified a polypeptide composed of 5 amino acid residues with a molecular weight of 604.95D, and its structure was N '-AEWCP-C' (Ala-Glu-Trp-Cys-Pro). The present invention is the first in many years to obtain a structurally defined component from an immunosuppressive component of the thymus. The pentapeptide is derived from TISE, and based on previous activity research on TISE, the invention can be used to prepare immunosuppressive drugs.

Description of drawings

Figure 1 shows the inhibitory effect of different drug concentrations on the proliferation of ConA-stimulated mouse spleen lymphocytes. ## indicates that compared with the blank group, p<0.01, there is a significant difference; ** indicates that compared with the ConA group, p<0.01, there is a significant difference.

Figure 2 is the inhibitory effect of different drug concentrations on the proliferation of LPS-stimulated mouse spleen lymphocytes. ## indicates that compared with the blank group, p<0.01, there is a significant difference; ** indicates that compared with the ConA group, p<0.01, there is a significant difference.

Figure 3 shows the toxicity of different concentrations of drugs on mouse spleen lymphocytes.

Figure 4 is the effect of different drug concentrations on the viability of RAW264.7 cells. ** indicates that there is a significant difference compared with the blank group, p<0.01.

Figure 5 shows the effects of different concentrations of drugs on the phagocytosis of RAW264.7 cells stimulated by LPS. # means compared with the blank group, p<0.05, there is a difference, ## means compared with the blank group, p<0.01, there is a significant difference; * means compared with the model group, p<0.05, there is a difference, ** Indicates that compared with the model group, p<0.01, there is a significant difference.

Figure 6 shows the effects of different concentrations of drugs on lung histology (HE staining) in ovalbumin (OVA)-induced mouse asthma model; a. Blank group (×100), b. Model group (×100), c. Ground Dexamethasone (Dex) (×100), d. TIPP10mg/kg (×100), e. TIPP50mg/kg (×100).

Fig. 7 is the effect of different concentrations of drugs on the content of IL-5 in alveolar lavage fluid of OVA-induced mouse asthma model. # means compared with the blank group, p<0.05, there is a difference, ## means compared with the blank group, p<0.01, there is a significant difference; * means compared with the model group, p<0.05, there is a difference, ** Indicates that compared with the model group, p<0.01, there is a significant difference.

detailed description

The present invention will be further described below in conjunction with the accompanying drawings and embodiments. It should be noted that the following description is only for explaining the present invention and not limiting its content.

A thymic immunosuppressive pentapeptide TIPP (thymicimmunosuppressivepentapeptide), derived from LMW-TISE-c (low molecular weight bovine thymus immunosuppressive extract), which is the amino acid sequence shown in SEQ ID NO.1:

Ala-Glu-Trp-Cys-Pro.

A polypeptide obtained by adding one or more of L-amino acid, D-amino acid, hydroxyl amino acid, methylated amino acid or heterocyclic amino acid from the N-terminal or C-terminal of the pentapeptide as the active center.

The heterocyclic amino acid is tryptophan, histidine or proline.

A cyclic peptide derivative obtained by linking the N-terminal and C-terminal of the pentapeptide to form a ring.

The compound obtained by acetylation, formylation of the N-terminal of the pentapeptide or aminoacylation or esterification of the C-terminal has greatly improved biological activity, half-life, stability, etc. compared with the pentapeptide.

Said alkylation is methylation, ethylation, propylation or butylation.

The esterification is an esterification reaction with methanol, ethanol, butanol, or hexanol.

An immunosuppressive drug, the active ingredient of which includes the application of the above-mentioned pentapeptide, polypeptide, cyclic peptide derivatives or compounds in the preparation of immunosuppressive drugs.

Application of the above-mentioned pentapeptide, polypeptide, cyclic peptide derivative or compound in the preparation of immunosuppressive drugs.

Example 1 The inhibitory effect of different concentrations of TIPP on the proliferation of mouse spleen lymphocytes

Male Balb/c mice at 6 to 8 weeks were sacrificed by cervical dislocation, soaked in 75% alcohol for 5 minutes, and the mice were taken out and placed in a sterile dish with the left side facing up. A small incision was made in the middle of the left ventral side of the mouse, the skin was torn off, and the abdominal wall was exposed. A red strip-shaped spleen was visible. Lift the peritoneum on the lower side of the spleen, cut it open and turn it up to expose the spleen, lift the spleen with tweezers, separate the connective tissue under the spleen with ophthalmic scissors, and take out the spleen. Put it into a Petri dish and wash it twice with 5mL of Hank's solution. Place the spleen on a stainless steel mesh (200 mesh), press the spleen gently with a syringe needle core, and rinse with 7-8mL of Hank's solution, collect the cell suspension in a 10mL sterile centrifuge tube, centrifuge at 1000r/min for 10min, discard the supernatant , add 8 mL of erythrocyte lysate, mix well, let stand for 5 min, centrifuge at 1000 r/min for 10 min, discard the supernatant, and wash once with 8 mL of Hank's solution. Finally, resuspend the cells in 5 mL of RPMI-1640 medium (containing 10% fetal bovine serum), count, and adjust the cell concentration to 2×10 ⁶ cells/mL. Inoculate in a 96-well plate, 100 μL/well, and set zero wells. The cells were stimulated to proliferate with ConA (final concentration 5 μg/mL) and lipopolysaccharide (LPS, final concentration 10 μg/mL) respectively. The grouping conditions were: blank group, simple ConA or LPS stimulation group, cyclosporin A (CsA) control group (ConA or LPS stimulation, CsA concentration was 0.1 μmol/L), different concentrations of TIPP effect group (ConA or LPS stimulation, The final concentrations of TIPP were 50 μmol/L, 100 μmol/L, 200 μmol/L, 300 μmol/L, 400 μmol/L, 500 μmol/L), and 5 replicate wells were set up in each group. After culturing for 68 hours at 37°C and 5% CO ₂ , add 20 μL of 5 mg/mL MTT to each well, continue culturing for 4 hours at 37°C and 5% CO ₂ , centrifuge at 3000 r/min for 10 min, and carefully suck the supernatant with a 1 mL syringe. Add 150 μL of DMSO, shake for 10 min, detect the OD value with a microplate reader at 570 nm, and use 630 nm as the reference wavelength.

The results are shown in Figure 1 and Figure 2. ConA and LPS can cause significant proliferation of splenic lymphocytes; and CsA, as a potent inhibitor of T cells, can significantly inhibit the proliferation of splenic lymphocytes caused by ConA and inhibit the proliferation of splenic lymphocytes caused by LPS. TIPP had no significant effect on the proliferation of splenic lymphocytes induced by ConA and LPS, and it was dose-dependent, and the inhibitory effect on the proliferation of splenic lymphocytes induced by ConA was more obvious.

The toxicity of embodiment 2 different concentration medicines to mouse spleen lymphocyte

Male Balb/c mice at 6 to 8 weeks were sacrificed by cervical dislocation, soaked in 75% alcohol for 5 minutes, and the mice were taken out and placed in a sterile dish with the left side facing up. A small incision was made in the middle of the left ventral side of the mouse, the skin was torn off, and the abdominal wall was exposed. A red strip-shaped spleen was visible. Lift the peritoneum on the lower side of the spleen, cut it open and turn it up to expose the spleen, lift the spleen with tweezers, separate the connective tissue under the spleen with ophthalmic scissors, and take out the spleen. Put it into a Petri dish and wash it twice with 5mL of Hank's solution. Place the spleen on a stainless steel mesh (200 mesh), press the spleen gently with a syringe needle core, and rinse with 7-8mL of Hank's solution, collect the cell suspension in a 10mL sterile centrifuge tube, centrifuge at 1000r/min for 10min, discard the supernatant , add 8 mL of erythrocyte lysate, mix well, let stand for 5 min, centrifuge at 1000 r/min for 10 min, discard the supernatant, and wash once with 8 mL of Hank's solution. Finally, resuspend the cells in 5 mL of RPMI-1640 medium (containing 10% fetal bovine serum), count them, adjust the cell concentration to 1× ¹⁰⁸ cells/mL, inoculate in a 96-well plate, 100 μL/well, and set a zero well. Different concentrations of TIPP were added, and 5 replicate wells were set up for each concentration. The concentrations are as follows: 0, 0.0064 μmol/L, 0.032 μmol/L, 0.16 μmol/L, 0.8 μmol/L, 4 μmol/L, 20 μmol/L, 100 μmol/L, 500 μmol/L. Incubate for 68 hours in a 37°C, 5% CO ₂ cell incubator. Add 20 μL of 5 mg/mLMTT, continue culturing at 37°C and 5% CO ₂ for 4 hours, then centrifuge at 3000 r/min for 10 minutes, remove the supernatant carefully with a 1 mL syringe, add 150 μL of DMSO to each well, shake for 10 minutes, detect the OD value with a microplate reader at 570 nm, and measure the OD value at 630 nm is the reference wavelength. Survival rate = (OD570nm of test group/OD570nm of normal group) × 100%.

The results are shown in Figure 3. After 68 hours of co-culture of splenic lymphocytes with TIPP, there was no significant difference in the survival rate compared with the group without TIPP, that is, TIPP had no obvious cytotoxicity to splenic lymphocytes.

Example 3 Inhibitory Effect of Different Concentrations of TIPP on RAW264.7 Cell Proliferation

Take RAW264.7 cells in the logarithmic growth phase cultured in DMEM medium (10% FBS), adjust the cell density to ² ×104/mL, inoculate on a 96-well plate with a volume of 100 μL per well, and place at 37°C, Cultivate for 2 h under 5% CO ₂ to make the cells adhere to the wall, and add different concentrations of TIPP (final concentrations are 25 μg/mL, 50 μg/mL, 100 μg/mL, 200 μg/mL, 400 μg/mL, and set 5 replicate wells for each concentration. ), with dexamethasone (Dex, final concentration 5 μg/mL) as the positive control, continue to culture for 48h. Add 20 μL of 5 mg/mLMTT to each well, continue culturing at 37 °C and 5% CO ₂ for 4 h, centrifuge at 3000 r/m for 10 min, carefully suck off the supernatant with a 1 mL syringe, add 150 μL of DMSO to each well, shake for 10 min, and detect with a microplate reader at 570 nm OD value, with 630nm as the reference wavelength.

The result is shown in Figure 4. When the concentration of TIPP is lower than 50μg/mL, the inhibition on the proliferation of RAW264.7 cells is small; and when the concentration is 100μg/mL and above, the inhibitory effect on the proliferation of RAW264.7 cells is obvious. According to the cytotoxicity grading table, when the relative proliferation rate of cells is greater than 100% or between 75% and 99%, the cytotoxicity is classified as grade 0 or grade 1, which is considered to have no cytotoxicity. When the relative proliferation rate of cells is 50% % to 74%, its cytotoxicity grade is 2, with mild toxicity. It can be seen from Figure 4 that when the concentration of TIPP is 200 μg/mL, the cell viability still reaches about 85%. It can be considered that TIPP has no cytotoxicity to RAW264.7 when the concentration of TIPP is ≦200 μg/mL; Grade 2, mildly toxic.

Example 4 Effects of different concentrations of drugs on the phagocytosis of RAW264.7 cells stimulated by LPS

Take RAW264.7 cells in the logarithmic growth phase, inoculate them on a 96-well plate, add 100 μL of cell suspension (2×10 ⁵ cells/mL) to each well, and culture in a 37°C, 5% CO ₂ incubator overnight. For supernatant, replace with 2.5% FBS DMEM culture medium, 100 μL/well. Grouping, blank control group: add 100 μL of DMEM culture solution with 2.5% FBS; model group: add LPS to make the final concentration 1 μg/mL; Dex group: add Dex (final concentration is 5 μg/mL) and LPS (final concentration is 1 μg/mL); administration group: 50 μL each of TIPP (final concentration 25 μg/mL, 50 μg/mL, 100 μg/mL, 200 μg/mL, 400 μg/mL) and LPS (final concentration 1 μg/mL), each group 5 replicate holes were set. After culturing in a 37°C, 5% _CO2 incubator for 24 hours, discard the supernatant, add 100 μL of 0.1% neutral red solution, incubate at 37°C, 5% _CO2 for 1 hour, discard the neutral red, and wash with pre-warmed PBS for 3 hours. Repeat, 200 μL each time, and blot dry. Add 200 μL/well of acetic acid-ethanol (volume ratio 1:1) cell lysate, let it stand overnight at 4°C, and measure the OD value at 490 nm with a microplate reader.

The result is shown in Figure 5. Compared with the blank group, the OD value of the LPS group was significantly different from that of the blank group, indicating that LPS can enhance the phagocytosis of RAW264.7 cells. Compared with the LPS group, the Dex group and 50, 100, 200, 400 μg/mL TIPP could all inhibit the LPS-stimulated RAW264.7 phagocytosis activity of neutral red, and when the TIPP concentration was 100 μg/mL, the OD value was the same as that of the blank group The levels are similar, indicating that when the concentration of TIPP is 100 μg/mL, it can completely inhibit the phagocytosis of macrophages induced by LPS.

The effect of embodiment 5 TIPP on the mouse model of asthma induced by OVA

SPF grade female Balb/c mice, 5-6 weeks, were randomly divided into 6 groups, 12 mice in each group, respectively blank group, model group, dexamethasone control group (3mg/kg), TIPP low-dose group (2mg/kg) kg), TIPP medium dose group (10mg/kg), TIPP high dose group (50mg/kg). Raised under the same conditions, the model group and the treatment group were intraperitoneally injected (i.p) 0.2 mL of Alu-Gel-S (SERVA Electrophoresis GmbH) containing 50 μg OVA (sigma, Grade V) on days 1, 7, and 14, and the blank group was i.p. normal saline. From the 28th day, the model group and the treatment group were challenged with 50 μL of 2 mg/mL OVA solution nasally, and the blank group was challenged with normal saline nasally. 1 hour before nasal drops, the blank group was subcutaneously injected (i.h) normal saline, the model group i.h normal saline, the dexamethasone group i.h dexamethasone (Dex, 3mg/kg), and the TIPP low, medium and high dose groups were respectively i.hTIPP2mg/ kg, 10mg/kg, 50mg/kg. When instilling the nose, anesthetize the mouse with ether until the mouse's body is weak and sagging, then instill the solution with 50 μL of normal saline or 50 μL of 2 mg/mL OVA solution, and let the solution be inhaled with the natural breathing of the mouse. On the 29th, 30th, 31st, 32nd, and 33rd day, repeated intranasal challenge was performed to establish a mouse model of asthma. Samples were collected within 24-48 hours after the last challenge. The mice were sacrificed by pulling the neck, fixed in the supine position, the neck skin was disinfected with 75% ethanol, and the chest cavity was opened for tracheal intubation. Ligate the left lung, and perform alveolar lavage on the right lung with 0.4mL of cold PBS to ensure the uniform expansion of the lungs. Slowly infuse each time and then withdraw slowly to recover the lavage fluid in a 1.5mLEP tube, repeat twice to ensure the recovery rate Reach 80% to 90%. Centrifuge at 4°C, 650×g for 5 minutes. The supernatant was aliquoted and stored at -80°C for cytokine detection. The left lung was taken, fixed with 4% formaldehyde solution, sectioned, and stained with HE.

The results are shown in Figure 6 and Figure 7. HE staining was performed on the lung tissue sections of the mice in each group. Compared with the normal group, the model group had mucosal congestion and edema, thickened mucosal layer, and inflammatory cell infiltration, a large amount of mucus in the lumen, and inflammatory cell infiltration around the bronchial wall. . In the Dex and TIPP administration group, the inflammation was significantly reduced, and only a small amount of inflammatory cells infiltrated around the bronchial wall. It shows that Dex and TIPP can inhibit the airway inflammation of asthmatic mice and inhibit the infiltration of inflammatory cells in the airway.

Fig. 7 is the effect of TIPP on IL-5 level in alveolar lavage fluid of asthmatic mice. IL-5 is a Th2 cytokine that is closely related to the development of asthma. It can promote the differentiation, survival and recruitment of eosinophils to the airway and assist B lymphocytes to produce antibodies. It can be seen from Figure 7 that compared with the blank group, the IL-5 level in the model group was significantly increased, and both Dex and TIPP could significantly reduce the IL-5 level in the alveolar lavage fluid.

Although the specific implementation of the present invention has been described above in conjunction with the accompanying drawings, it does not limit the protection scope of the present invention. On the basis of the technical solution of the present invention, those skilled in the art can make various Modifications or variations are still within the protection scope of the present invention.

Claims (3)

1. pentapeptide, polypeptide, Cyclopeptide derivatives or compound are preparing the application in immunosuppressive drug, it is characterized in that:

Described suppression is the phagolysis of the scavenger cell suppressed because of LPS induction;

Or described suppression is suppress inflammatory cell in the infiltration of air flue;

Or described suppression is for suppressing RAW264.7 cell proliferation;

Wherein, described pentapeptide is the aminoacid sequence as shown in SEQIDNO.1: Ala-Glu-Trp-Cys-Pro; Described polypeptide: with described pentapeptide for active centre, holds from its N or C holds the one or more polypeptide obtained added L-amino acid, D-amino acid, hydroxy-amino-acid, methylated amino-acid or heterocyclic amino acid; Described Cyclopeptide derivatives: to be held by the N of described pentapeptide or polypeptide and C end connects into the Cyclopeptide derivatives that ring obtains; Described compound: hold through acetylize, formylation, alkylation or C the compound obtained through aminoacylation, esterification by the N end of described pentapeptide or polypeptide.

2. apply as claimed in claim 1, it is characterized in that: when suppressing the phagolysis because of the scavenger cell of LPS induction, the inhibition concentration of described medicine is 100 μ g/mL or 200 μ g/mL or 400 μ g/mL.

3. apply as claimed in claim 1, it is characterized in that: when suppressing RAW264.7 cell proliferation, the inhibition concentration of described medicine is 400 μ g/mL.