CN108721621B - Small molecular compound for inhibiting hepatic fibrosis and application thereof - Google Patents
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Abstract
本发明涉及抑制肝纤维化的小分子化合物及应用。本发明人筛选获得了一系列对于原代HSC的PI4KA(编码PI4KIIIα)的表达或PI4KIIIα的酶活性具有抑制作用的化合物，这些化合物均能较为显著地抑制HSC的PI4KA的mRNA水平或抑制PI4KIIIα的酶活性，进而减低α‑SMA或I型胶原的mRNA水平，从而可以抑制肝纤维化。The present invention relates to small molecule compounds and applications for inhibiting liver fibrosis. The inventors screened and obtained a series of compounds that have inhibitory effects on the expression of PI4KA (encoding PI4KIIIα) in primary HSCs or the enzymatic activity of PI4KIIIα, and these compounds can significantly inhibit the mRNA level of PI4KA in HSCs or inhibit the enzymes of PI4KIIIα Activation of α-SMA or collagen type I mRNA levels, thereby inhibiting liver fibrosis.
Description
Technical Field
The invention belongs to the field of biological medicines, and particularly relates to a small molecular compound for inhibiting hepatic fibrosis and application thereof.
Background
Hepatic fibrosis is a reversible liver callus repair reaction that occurs when the liver is damaged, and is mainly represented by accumulation of extracellular matrix (ECM). When liver damage continues to occur, the continued accumulation of ECM results in replacement of liver parenchyma by callus, eventually leading to cirrhosis. Accumulation of ECM is closely associated with activation of Hepatic Stellate Cells (HSCs), and HSCs have been the primary target cells for prevention and treatment of hepatic fibrosis. There are studies that indicate that HSC activation is regulated by the PI3K/Akt pathway. PI3K is an intracellular phosphatidylinositol kinase that has regulatory effects on cell growth, proliferation, and differentiation. Research shows that the PI3K/Akt signal channel can promote the activation and proliferation of HSC, thereby promoting liver cirrhosis. Phosphatidylinositol 4-kinases (PI 4KIII alpha) catalyze phosphorylation of inositol Phosphate (PI) at position D4 to produce phosphatidylinositol 4-phosphate (4-phosphatyl-inositide, PI)4P)，PI4The P is catalyzed by PIP5-K kinase to generate 4, 5-diphosphatil-inosidediphosphate，PIP2). And PIP2The protein is a direct catalytic substrate of PI3K, can activate the activity of a plurality of downstream proteins, and is in a central position in PI3K/Akt, so that PI4KIII alpha can influence a PI3K/Akt signal channel.
Despite the research on the PI3K/Akt signaling pathway in the art, there is still a lack of effective therapeutic agents for liver fibrosis or cirrhosis.
Disclosure of Invention
The invention aims to provide a small molecular compound for inhibiting hepatic fibrosis and application thereof.
In a first aspect of the invention, the use of a PI4KIII α inhibitor for the preparation of a medicament for inhibiting liver fibrosis or cirrhosis (including preventing, alleviating or treating liver fibrosis or cirrhosis diseases) is provided.
In another aspect of the present invention, there is provided a pharmaceutical composition for inhibiting liver fibrosis or cirrhosis (including preventing, alleviating or treating liver fibrosis or cirrhosis diseases), comprising: small molecule compounds that specifically inhibit PI4KIII α; and a pharmaceutically acceptable carrier.
Other aspects of the invention will be apparent to those skilled in the art in view of the disclosure herein.
Drawings
Figure 1, overall appearance of normal liver (CTRL), Cirrhosis liver (Cirrhosis) and HE stained paraffin sections.
A and E are the overall appearance of the liver of CTRL and Cirrhosis mice respectively, and B, E are magnified images of a rectangular part in A, D respectively; C. f is the result after HE staining of liver pathology sections of CTRL and Cirrhosis mice, respectively, where the black arrows indicate inflammatory vesicles.
FIG. 2, Cirrhosis-PI4KA-/+Graph comparing the liver surface of mice with that of Cirrhosis mice. A, B, C and D, E, F are enlarged images of rectangular portions of A, B, C, respectively, of the entire appearance of the liver.
FIG. 3, Normal liver (CTRL), liver Cirrhosis (Cirrhosis), PI4KA Single copy knockoutMouse liver Cirrhosis liver (Cirrhosis-PI4 KA)-/+) HE stained paraffin sections.
Figure 4, statistics of the number of inflammatory vesicles around the venous sinuses of normal liver (CTRL), hepato-hardened liver (Cirrhosis), PI4KA single copy knockout mice.
Detailed Description
The inventor screens and obtains a series of compounds with inhibiting effect on the expression of PI4KA of primary HSC through intensive research, and the compounds can inhibit the mRNA level of PI4KA more obviously, so that the hepatic fibrosis can be inhibited.
PI4KIII alpha inhibitors
Based on the new discovery of the inventor, the PI4KIII alpha inhibitor can be used for preparing a composition for preventing, improving or treating liver cirrhosis or liver fibrosis.
As used herein, the term "PI 4KIII α inhibitor" includes "activity or function inhibitors" thereof, and also includes nucleic acid inhibitors, antagonists, inhibitors, blockers, etc. of PI4KIII α, so long as they are capable of down-regulating the expression level of PI4KIII α inhibitors, inhibiting the activity or function of PI4KIII α inhibitors. They may be chemical compounds, chemical small molecules, biological molecules. The biomolecule may be at the nucleic acid level (including DNA, RNA) or at the protein level.
The PI4KIII alpha inhibitor refers to any substance which can reduce the activity of PI4KIII alpha, reduce the stability of PI4KIII alpha, reduce the expression of PI4KIII alpha and reduce the effective action time of PI4KIII alpha, and the substances can be used for the invention, and can be used as substances which are useful for reducing PI4KIII alpha, thereby being used for relieving or treating liver cirrhosis or liver fibrosis. For example, the down-regulating agent is: nucleic acid inhibitors, protein inhibitors, antibodies, ligands, compounds, nucleases, nucleic acid binding molecules, and the like, provided that they are capable of downregulating the expression, inhibiting the activity or function of PI4KIII α. Such nucleic acid inhibitors include, but are not limited to: shRNA, antisense nucleic acid, small interfering RNA, micro RNA or a construct capable of expressing or forming shRNA, antisense nucleic acid, small interfering RNA and micro RNA by using a PI4KIII alpha coding gene or a transcript thereof as an inhibition or silencing target.
Compounds with inhibitory action
After a large number of screens, the invention provides a series of compounds with inhibiting effect on the expression of alpha-SMA or type I collagen of primary HSC, in particular to compounds listed in No. 1-32 in Table 1. More preferred are compounds having "+ + +" or "+ + + +"; of these, "+ + + + +" compounds are most preferred.
The present invention also includes isomers, solvates, precursors of the above compounds, or pharmaceutically acceptable salts thereof, as long as they also have the function of inhibiting PI4KIII α. The term "pharmaceutically acceptable salt" refers to a salt formed by reacting a compound with an inorganic acid, an organic acid, an alkali metal, an alkaline earth metal or the like. These salts include (but are not limited to): (1) salts with the following inorganic acids: such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid; (2) salts with organic acids such as acetic acid, oxalic acid, succinic acid, tartaric acid, methanesulfonic acid, maleic acid, or arginine. Other salts include those formed with alkali or alkaline earth metals (e.g., sodium, potassium, calcium or magnesium), in the form of esters, carbamates, or other conventional "prodrugs". The compounds have one or more asymmetric centers. Thus, these compounds may exist as racemic mixtures, individual enantiomers, individual diastereomers, mixtures of diastereomers, cis or trans isomers.
By "precursor of a compound" is meant that, when administered by an appropriate method, the precursor of the compound undergoes a metabolic or chemical reaction in the patient to convert the compound to a compound that inhibits PI4KIII α activity as claimed herein.
It will be understood by those skilled in the art that, once the structure of the compounds of the present invention is known, the compounds of the present invention can be obtained by a variety of methods well known in the art, using well known starting materials, such as chemical synthesis or extraction from organisms (e.g., animals or plants), which are encompassed by the present invention.
Pharmaceutical composition
The invention also provides a pharmaceutical composition comprising an effective amount of the compound, and a pharmaceutically acceptable carrier. The pharmaceutical composition can be used for preventing, relieving or treating hepatic fibrosis or liver cirrhosis by inhibiting the expression or activity of PI4 KA.
As used herein, a "pharmaceutically acceptable" ingredient is one that is suitable for use in humans and mammals without adverse side effects (such as toxicity, irritation, and allergic response), i.e., at a reasonable benefit/risk ratio. The term "pharmaceutically acceptable carrier" refers to a carrier for administration of a therapeutic agent, including various excipients and diluents.
As used herein, the term "pharmaceutical composition" includes (but is not limited to): pharmaceutical, dietary supplement, nutraceutical compositions, as long as they contain said compounds of the invention, as active ingredients for the prevention, amelioration or treatment of liver fibrosis or cirrhosis in mammals and humans.
In the present invention, the term "comprising" means that various ingredients can be used together in the mixture or composition of the present invention. Thus, the terms "consisting essentially of and" consisting of are encompassed by the term "comprising.
Pharmaceutically acceptable carriers in the pharmaceutical compositions of the present invention include (but are not limited to): olive oil, saline, buffer, glucose, water, glycerol, and combinations thereof. Generally, the pharmaceutical formulation should be compatible with the mode of administration. The pharmaceutical composition is preferably manufactured under sterile conditions. The amount of active ingredient administered is a therapeutically effective amount.
The dosage form of the pharmaceutical composition of the present invention may be various, as long as it is a dosage form that allows the active ingredient to efficiently reach the body of a mammal or a human. Such as may be selected from: tablets, capsules, powders, granules, syrups, solutions, suspensions, or aerosols.
The pharmaceutical composition of the present invention may also be used in combination with other one or more substances effective for diabetes or metabolic syndrome, if necessary.
It is to be understood that the invention is not limited to the particular methodology described herein, including protocols, analytical test methods and reagents, etc., which may vary.
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, for which specific conditions are not noted in the following examples, are generally performed according to conventional conditions such as those described in J. SammBruk et al, molecular cloning protocols, third edition, scientific Press, 2002, or according to the manufacturer's recommendations.
Materials and methods
Materials (I) and (II)
1. Laboratory animal
SPF mice, weighing about 30g, were fed on normal diet and free diet from the southern model animal center in China.
2. Primary reagents and instruments
Chloral hydrate, Paraformaldehyde (PFA), Phosphate Buffered Saline (PBS), ethanol, xylene, paraffin, a paraffin embedding machine, a paraffin slicer, an embedding box and a developing tank.
Second, method
1. Single copy deleted mice (PI 4K)-/+) Preparation of
Single copy deletion mice (PI 4K) were prepared by the following method-/+)：
PI4KIII alpha heterozygous mutation (Pi4 ka)Gt(RRO073)Byg/+): the insertion of the transposon pGT2Lxf into the PI4KA (encoding PI4KIII alpha) gene can cause the copy gene to be obstructed in transcription, and the generated mRNA can only translate the fusion protein consisting of the first 1-265 amino acids at the amino terminal of the PI4KIII alpha and the protein encoded by the reporter gene).
Pi4kaGt(RRO073)Byg/+The mutant heterozygote (MMRRC, Cat. #016351-UCD) was mated with C57BL/6 wild-type mice to obtain wild-type (CTRL) and PI4KIIIa mutant heterozygotes (PI4 KA)-/+)。
2. Using CCl4Method for constructing hepatic fibrosis mouse by assisting ethanol
Six mice of about 30g are taken as a group, and each group is injected with 20 percent of the total weight according to 0.2 mL/abdominal cavityCCl4Rapeseed oil solution is administered 2 times a week for 7 weeks for 14 times, and the first two weeks use 10% ethanol solution as drinking water; and changing to 20% ethanol solution as drinking water in 3-4 weeks, and taking 30% ethanol solution as drinking water from 5 weeks until the hepatic fibrosis mouse is constructed, and inducing for 7 weeks. When the mice in the test group are administrated, the control group is injected with physiological saline with the same amount, and is fed with common pellet feed and normally drinks water.
Wild mouse and PI4KA single copy deletion mouse are constructed by the method to obtain wild hepatic fibrosis mouse (Cirrhosis) and PI4KA single copy deletion hepatic fibrosis mouse (Cirrhosis-PI 4K)-/+)。
3. Dissection and perfusion of mice
Anaesthetizing a mouse by using 0.02mL/g 4% chloral hydrate, fixing the mouse on a bracket in a lying manner, cutting the mouse from the abdominal cavity of the mouse to the diaphragm, carefully cutting the diaphragm without cutting blood vessels, then exposing the heart on the tip, cutting ribs if necessary, inserting a needle from the left ventricle of the heart, cutting the right auricle, injecting 20-30mL of PBS to replace the whole blood in the mouse, observing that the liver of the mouse is whitened, injecting 20mL of 4% PFA PBS diluent solution for fixing after no blood streak exists, taking down the whole liver, and fixing for 48 hours in the 4% PFA solution.
4. Observation of the overall morphology of the liver
After the mouse dissection and perfusion are completed, the complete liver is taken out and arranged on a black flat plate in a horizontal mode, light is well controlled, and a camera is arranged right above the black flat plate for shooting and observation.
5. Pathological section of liver
Liver tissue blocks of 50mm by 50mm in volume were excised from the largest liver lobe of the mouse and placed in an embedding cassette. After that, the fixed solution of the liver tissue was sufficiently eluted by washing with running water for one hour.
Then, the dehydration and embedding process is carried out, the embedding box filled with the liver tissue block is placed into 60% ethanol I, 60% ethanol II, 75% ethanol I, 75% ethanol II, 85% ethanol I, 85% ethanol II, 95% ethanol I, 95% ethanol II, absolute ethanol I and absolute ethanol II to be respectively soaked for 30min, then the embedding box is placed into dimethylbenzene I and dimethylbenzene II to be respectively soaked for 5min, and finally the embedding box is placed into paraffin I for 60min and paraffin II for 90 min. Then the embedding box is opened, and the liver tissue block is clamped out and embedded by an embedding machine.
The wax block was stored at-20 ℃ for a while before slicing, taken out during slicing, sliced with a paraffin slicer, and 0.4 μm cut.
And (3) placing the cut wax sheets into a sheet spreading groove filled with water at 38 ℃ for spreading. And fishing the slide by using a clean slide after the slide is unfolded. Finally, the slide is placed on a 60 ℃ baking device for baking for one hour. After the baking of the slices is finished, the slices can be stored at normal temperature for later experiments.
6. HE staining
The deparaffinized tissue was stained with Harri hematoxylin stain for 6min at room temperature, hydrochloric acid ethanol solution for 5s, eosin stain for 1min, and mounted on neutral resin.
7. Isolation and culture of rat Primary Hepatic Stellate Cells (HSC)
Male adult SD rats, weighing about 400g, anesthetized with sodium pentobarbital under sterile conditions, were cannulated for portal vein irrigation with D-Hank's perfusion rinse, while the liver was free; taking out the liver, placing in a sterile culture dish, cutting, removing structures such as fascia and the like, transferring into D-Hank's solution containing 0.5g/L type IV collagenase and 0.1g/L protease E, carrying out water bath at 37 ℃, and carrying out shaking digestion. The cell suspension is screened by a 200-mesh cell screen, centrifuged, washed by DMEM for 2-3 times, centrifuged by 180g/L Nycodenz gradient, a middle cloudy cell layer is taken for cell counting, and the cell concentration is adjusted to be 1x10 by DMEM culture solution containing 20% fetal calf serum5The density of each well is inoculated on a 6-well plastic culture plate without coating, and the culture plate is placed at 37 ℃ and the volume fraction of CO is 5 percent2CO of 95% humid air2Culturing in an incubator. After 24h, the culture solution was changed to DMEM containing 10% fetal calf serum, and then changed 1 time every 2-3d according to the growth of the cells.
8. Screening for the Effect of PI4KIIIa inhibitors on HSC activation
Primary HSC and at 5X 104The density of each hole is inoculated in a 12-hole plate, each hole is 1ml, and each group has 3 multiple holes; respectively at 50nmolThe candidate substance (table 1) with/L concentration is used for treating primary HSC cultured on the 4 th day, a blank control group is arranged, cells are collected after 72 hours of action, and the confluence of the cells is 40-80% when cell RNA of each group is extracted for analysis.
9. RNA extraction and Real-time PCR analysis
Total cellular RNA was extracted according to Trizol Reagent instructions and purity and quantification was measured by UV spectrometer. The cDNA is synthesized by 20ul reverse transcription system, reverse transcription PCR is carried out to design primer according to GenBank data, and prepared standard substance is used as template to determine optimal reaction system and reaction condition. SYBR Green-1 fluorescent quantitative PCR amplification was carried out with glyceraldehyde monophosphate dehydrogenase (GAPDH) as an internal control, 20ul of PCR system containing cDNA2ul, 1ul each of upstream and downstream primers (10umol/L), and 10ul of SYBR Premix Ex Taq enzyme, supplemented to 20. mu.l with DEPC water.
The reaction program conditions are set in an ABI 7500 Real-time PCR instrument as follows: pre-denaturation at 95 ℃ for 30s for 1 cycle, PCR amplification reaction at 95 ℃ for 5s for 40 cycles, 60 ℃ for 34s for 40 cycles, 95 ℃ for 15s for 1 cycle. The target gene and the reference gene of each sample are subjected to amplification reaction respectively.
The amplification curves and parameter amplification reactions of the target genes and the reference genes of the samples are directly generated by a machine after the reaction is finished.
GAPDH primer:
upstream: 5'-GAG GAC CAG GTT GTC TCC TG-3' (SEQ ID NO: 1);
downstream: 5'-GGA TGG ATT GTG AGG GAG A-3' (SEQ ID NO: 2);
alpha-SMA primer:
upstream: 5'-GGT GAA ACT CTG GAG ATC CT-3' (SEQ ID NO: 3);
downstream: 5'-AAT GGC ATC TGT GTC AAC C-3' (SEQ ID NO: 4).
10. Statistical treatment
Statistical analysis is carried out by using an SPSS11.0 software package, all data are subjected to normality and variance homogeneity test, the measured data are represented by X +/-SD, the comparison between the two groups adopts t test, and P <0.05 represents that the difference has statistical significance.
Example 1 construction of hepatic fibrosis mice
To verify the inhibitory effect of PI4KIII alpha down-regulation on hepatic fibrosis, the inventors of the present invention utilized CCl4The method of (1) establishes a mouse hepatic fibrosis model. The model makes use of CCl4And the damage effect of ethanol on liver cells, so as to force liver tissues of mice to generate hepatic fibrosis lesion. In the process of continuously repairing the liver injury, the fibrosis degree of the liver is continuously enhanced, so that the liver is excessively fibrotic, and finally, cirrhosis is developed. In mice with hepatic fibrosis, hepatocytes of the mice are damaged, and liver function is impaired. The establishment condition of a mouse hepatic fibrosis model is judged by observing the damage of the liver after the tissue section of the liver.
After modeling, the liver of a control group wild-type mouse (CTRL) and liver fibrosis mouse (Cirrhosis) is dissected out and compared, and the liver surface of the CTRL mouse is smooth and flat, while the liver surface of the Cirrhosis mouse is rough and granular.
After two groups of mice are subjected to histopathological section respectively, observation shows that the CTRL mice have compact and regular liver cell arrangement, smooth and plump cells around venous sinuses and less vacuolated inflammation; in Cirrhosis mice, the liver cells are loosely arranged, and some vacuolated inflammatory vesicles appear near the venous antrum, as shown in fig. 1, and the number of inflammatory vesicles is also significantly increased (P <0.0001), as shown in fig. 4.
The results of the above studies indicate that CCl is used4The method of taking ethanol solution as drinking water can effectively construct mouse liver fibrosis model.
Example 2 Down-regulation of PI4KIII alpha has an effect on hepatic fibrosis in mice
In order to find a biological medicine suitable for inhibiting hepatic fibrosis, the inventor finds that the down-regulation of PI4KIII alpha has an effect on hepatic fibrosis of mice through a large amount of screening.
As previously described, the present inventors have constructed Cirrhosis mice and Cirrhosis-PI4KA-/+As a result, it was found that Cirrhosis-PI4KA-/+Fibrosis of mouse liver was significantly alleviated compared to Cirrhosis mice.
From the liver as a whole, Cirrhosis-PI4KA-/+Liver of mouseVisceral surface in comparison to Cirrhosis mice
The surface of the liver is smoother as shown in fig. 2.
From pathological section, Cirrhosis-PI4KA-/+The arrangement of liver cells in mice was more regular and compact compared to Cirrhosis mice, as shown in figure 3.
The inflammatory vesicles near the sinus venosus were observed and were also found to be significantly reduced (P ═ 0.0085, P ═ 0.0006), as shown in fig. 4.
From the overall inhibition, the single copy deletion of PI4KA significantly inhibited the progression of liver fibrosis in mice. Thus, a single copy deletion of PI4KA can effect treatment of liver fibrosis
And (4) inhibiting.
Example 3 screening of Compounds having inhibitory Effect on Primary HSC
The magnitude of the inhibition of HSC activation by some potential candidates was determined by the degree of downregulation of the mRNA levels of a-SMA in the treated group relative to the blank control group following administration.
Screening conditions are as follows: the degree of mRNA level down-regulation for inhibition of PI4KA was > 70%, 30-70%, < 30%,
the action intensities of inhibiting HSC activation are +++, ++, and ++, respectively.
After screening a large number of candidate compounds, some compounds having inhibitory effect on the expression of PI4KA of primary HSC are listed in table 1, and all of these compounds can significantly inhibit the mRNA level of PI4KA, so as to inhibit liver fibrosis.
TABLE 1 Compounds and their inhibitory Effect on Primary HSCs
All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.
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