CN116768974A - Polypeptide compound for preventing and/or treating renal fibrosis - Google Patents

Polypeptide compound for preventing and/or treating renal fibrosis Download PDF

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CN116768974A
CN116768974A CN202210236822.4A CN202210236822A CN116768974A CN 116768974 A CN116768974 A CN 116768974A CN 202210236822 A CN202210236822 A CN 202210236822A CN 116768974 A CN116768974 A CN 116768974A
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thr
compound
arg
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trp
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蒋先兴
余欢
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Sun Yat Sen University
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/08—Peptides having 5 to 11 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
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    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/64—Cyclic peptides containing only normal peptide links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

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Abstract

The present invention discloses a polypeptide compound for treating and/or preventing renal fibrosis, the polypeptide compound comprising: thr-His-His-Arg-Pro-Trp-Thr-NH 2 A parent peptide represented; or a polypeptide compound derived from a parent peptide, which is obtained by substituting any one of amino acids at positions 1 to 7 in the parent peptide with Ala, or substituting any one of amino acids at positions 2 to 5 with Lys or D-type amino acid, or deleting Thr at position 1 or/and His at position 2, or acetylating the N-terminus. The polypeptide compound of the invention has the characteristics of high bioactivity, no adverse reaction and the like, can obviously improve kidney damage, and can be preparedFor use in the prevention and/or treatment of renal fibrosis.

Description

Polypeptide compound for preventing and/or treating renal fibrosis
Technical Field
The invention belongs to the technical field of biochemistry, and particularly relates to a polypeptide compound for preventing and/or treating renal fibrosis.
Background
Fibrosis is characterized by the loss of capillary networks and aggregation of fibrous collagen, activated myofibroblasts, and inflammatory cells. In kidney fibrosis, tubular Epithelial Cells (TECs) are lost due to cell death, and the remaining cells dedifferentiate, resulting in reduced expression of the characteristic epithelial marker, increased expression of the mesenchymal marker (Kang HM, ahn SH, choi P, koYA, han SH, chinga F, park AS, tao J, shalma K, pullman J, bottinger EP, goldberg IJ, susztak K.deffective fatty acid oxidation in renal tubular epithelial cells has a key role in kidney fibrosis development. Nat Med.2015Jan;21 (1): 37-46.). Chronic Kidney Disease (CKD) affects nearly 10% of adults in the united states, and the incidence and prevalence of the disease is rising worldwide. CKD progresses to end-stage renal disease, with progressive decline in renal function as the number of functional nephrons of interest is lost. Treatment options for CKD are limited and only provide partial protection against CKD progression. Thus, developing more effective drugs to stop CKD progression is a key challenge for public health (Zhang ZH, he JQ, zhao YY, chen HC, tan nh.aseptic acid prevents renal fibrosis in UUO rats via promoting the production of d-PGJ2, an endogenous ligand of PPAR- γ. Acta Pharmacol sin.2020mar;41 (3): 373-382).
Renal fibrosis is the final co-manifestation of all forms of end-stage Chronic Kidney Disease (CKD), mainly associated with cardiovascular disease such as age, obesity, diabetes, hypertension, etc. Pathophysiology of renal fibrosis can be divided into four overlapping phases: initiation, activation, execution, and progression. Although there is no clear limit between these four phases, each phase is associated with a specific molecular and cellular mechanism (Zhang X, ritter JK, li N.Sphingosine-1-phosphate pathway in Renal fibrins.am J Physiol Renal physiol.2018 Oct 1;315 (4): F752-F756.). The occurrence mechanism of kidney fibrosis is: the different organs are mostly dominated by localized epithelial lesions before fibrosis develops. Exposure of epithelial cells to toxins can lead to the development of tissue fibrosis, highlighting the pathogenicity of epithelial lesions, and also indicating that epithelial-mesenchymal cell signaling is also the primary mechanism responsible for most of the interstitial fibrotic nephropathy in the important epithelial-mesenchymal transition (epithelial mesenchymallransition, EMT) that promotes fibrosis. Studies have been conducted on kidney tissue biopsies from 133 renal patients to find that there is epithelial-to-mesenchymal transition of epithelial tubular cells in most patients except for histological lesions, and more importantly that the extent of EMT extension is closely related to the extent of interstitial lesions (Wang Jinrong, xiong Yangyang, lichao, yoga, kong Juan. Progress of renal fibrosis [ J ]. Journal of medical research, 2015,44 (06): 158-160.). Renal fibrosis (RIF) is a pathological consequence of excessive deposition of extracellular matrix following many pathogenic factors leading to aberrations in cytokines, signaling pathways, etc., which may be one of the leading causes of the development of RIF. TGF-beta/Smad, TLR4, wnt/beta-catenin, notch, etc. are currently the major signaling pathways studied to lead to the occurrence of RIF (Legenamine, zhang Shi, yu Xueqin, chen Fang, mei Yi. Progress of research on the role of signaling pathways in the mechanism of renal fibrosis [ J ]. Shandong medicine, 2020,60 (02): 102-105.).
There is no drug currently available that can fully treat kidney fibrosis, and therefore, there is a real need to provide a novel polypeptide compound for treating kidney fibrosis.
Disclosure of Invention
The invention aims to provide a polypeptide compound for treating and/or preventing renal fibrosis, which has biological activity in improving renal fibrosis and can be used for treating or preventing renal fibrosis effects, and application and pharmaceutical compositions thereof.
To achieve the above object, the present invention provides a polypeptide compound comprising:
Thr-His-His-Arg-Pro-Trp-Thr-NH 2 (SEQ ID NO: 1) a parent peptide; or alternatively
A polypeptide compound derived from the parent peptide, wherein any of the 1 st to 7 th amino acids in the parent peptide is substituted by Ala, or any of the 2 nd to 5 th amino acids is substituted by Lys or D-type amino acid, or Thr 1 st or/and His 2 nd or N-terminal is/are deleted, or an N-terminal is acetylated.
The polypeptide compound of the present invention is a linear peptide or a cyclic peptide formed by linking Thr at position 1 and Thr at position 7 in the amino acid sequence by amide bond formation.
In one embodiment, the amino acid sequence of the polypeptide compound is selected from any one of the following amino acids 1 to 7 in the parent peptide of the present invention after substitution with Ala:
compound 2 (SEQ ID NO: 2):
Ala-His-His-Arg-Pro-Trp-Thr-NH 2 ；
compound 3 (SEQ ID NO:3)：
Thr-Ala-His-Arg-Pro-Trp-Thr-NH 2 ；
Compound 4 (SEQ ID NO: 4):
Thr-His-Ala-Arg-Pro-Trp-Thr-NH 2 ；
compound 5 (SEQ ID NO: 5):
Thr-His-His-Ala-Pro-Trp-Thr-NH 2 ；
compound 6 (SEQ ID NO: 6):
Thr-His-His-Arg-Ala-Trp-Thr-NH 2 ；
compound 7 (SEQ ID NO: 7):
Thr-His-His-Arg-Pro-Ala-Thr-NH 2 the method comprises the steps of carrying out a first treatment on the surface of the Or (b)
Compound 8 (SEQ ID NO:8)：
Thr-His-His-Arg-Pro-Trp-Ala-NH 2 。
In one embodiment, the parent peptide of the invention lacks Thr 1 or/and His 2, and the amino acid sequence of the polypeptide compound is selected from any one of the following:
compound 9 (SEQ ID NO: 9):
His-His-Arg-Pro-Trp-Thr-NH 2 the method comprises the steps of carrying out a first treatment on the surface of the Or (b)
Compound 10 (SEQ ID NO:10)：
His-Arg-Pro-Trp-Thr-NH 2 。
In one embodiment, any of amino acids 2 to 5 of the parent peptide of the present invention is substituted with Lys, and the amino acid sequence of the polypeptide compound is selected from any one of the following:
compound 11 (SEQ ID NO: 11):
Thr-Lys-His-Arg-Pro-Trp-Thr-NH 2 ；
compound 12 (SEQ ID NO: 12):
Thr-His-Lys-Arg-Pro-Trp-Thr-NH 2 ；
compound 13 (SEQ ID NO: 13):
Thr-His-His-Lys-Pro-Trp-Thr-NH 2 the method comprises the steps of carrying out a first treatment on the surface of the Or (b)
Compound 14 (SEQ ID NO: 14):
Thr-His-His-Arg-Lys-Trp-Thr-NH 2 。
in one embodiment, the N-terminus of the parent peptide of the invention is acetylated, and the amino acid sequence of the polypeptide compound is:
compound 15 (SEQ ID NO: 15):
Ac-Thr-His-His-Arg-Pro-Trp-Thr-NH 2 。
in one embodiment, the parent peptide of the invention is acetylated at the N-terminus and the amino acid His at position 2 is substituted with D-His, the amino acid sequence of the polypeptide compound is:
compound 16 (SEQ ID No. 16):
Ac-Thr-(D-His)-His-Arg-Pro-Trp-Thr-NH 2 。
in one embodiment, the parent peptide of the invention is acetylated at the N-terminus and the amino acid His at position 3 is substituted with D-His, the amino acid sequence of the polypeptide compound is:
compound 17 (SEQ ID NO: 17):
Ac-Thr-His-(D-His)-Arg-Pro-Trp-Thr-NH 2 。
in one embodiment, the N-terminus of the parent peptide of the present invention is acetylated and the amino acid Arg at position 4 is substituted with D-Arg, the amino acid sequence of the polypeptide compound is:
compound 18 (SEQ ID NO: 18):
Ac-Thr-His-His-(D-Arg)-Pro-Trp-Thr-NH 2 。
in one embodiment, the N-terminus of the parent peptide of the invention is acetylated and amino acid Pro at position 5 is substituted with D-Pro, the amino acid sequence of the polypeptide compound is:
compound 19 (SEQ ID NO: 19):
Ac-Thr-His-His-Arg-(D-Pro)-Trp-Thr-NH 2 。
in one embodiment, the polypeptide compound of the invention is a cyclic peptide having an amino acid sequence selected from any one of the following:
compound 20 (SEQ ID NO: 20):
compound 21 (SEQ ID No. 21):
the invention also provides application of the polypeptide compound in preparing a medicament for preventing or directly or indirectly treating renal fibrosis or a disease characterized by the renal fibrosis.
Renal fibrosis (renal fibrosis) is a common pathway by which chronic kidney disease ultimately leads to end-stage renal failure. Conditions characterized by renal fibrosis include: chronic glomerulonephritis, chronic pyelonephritis, obstructive nephropathy, systemic lupus erythematosus nephrosis, hereditary nephropathy such as Alport syndrome, diabetic nephropathy, hypertensive nephropathy, drug-induced nephropathy, nephropathy caused by hepatitis B or AIDS virus, and kidney transplantation.
The invention also provides a pharmaceutical composition containing the polypeptide compound, which is prepared by taking the polypeptide compound as an active ingredient and adding at least one pharmaceutically acceptable carrier and/or auxiliary material.
Those skilled in the art will appreciate that the pharmaceutical compositions of the present invention are suitable for various modes of administration, such as oral administration, transdermal administration, intravenous administration, intramuscular administration, topical administration, nasal administration, and the like. Depending on the mode of administration employed, the polypeptide pharmaceutical compositions of the present invention may be formulated into a variety of suitable dosage forms comprising at least one effective amount of a polypeptide of the present invention and at least one pharmaceutically acceptable pharmaceutical carrier.
Examples of suitable dosage forms are tablets, capsules, sugar-coated tablets, granules, oral solutions and syrups, ointments and patches for skin surfaces, aerosols, nasal sprays, and sterile solutions which can be used for injection.
Pharmaceutical compositions containing the polypeptide compounds of the invention may be formulated as solutions or lyophilized powders for parenteral administration, the powders being reconstituted by the addition of appropriate solvents or other pharmaceutically acceptable carriers prior to use, liquid formulations typically being buffers, isotonic solutions and aqueous solutions.
The amount of the polypeptide compound of the present invention used in the pharmaceutical composition may vary widely, and can be easily determined by those skilled in the art according to objective factors such as the kind of disease, the severity of the disease, the weight of the patient, the dosage form, the administration route, etc.
The invention has the advantages that:
1) The polypeptide compound of the invention has good biological activity;
2) In drug substitution experiments of drugs, the polypeptide compound of the invention has good stability, is easy to scale-up production and has low cost;
3) Compared with small molecular compounds, the polypeptide compound has lower toxicity, larger safety window and smaller dosage;
4) Through a great deal of experimental study, the inventor proves that the polypeptide compound has obvious therapeutic effect on renal fibrosis, and the polypeptide compound can be used for directly or indirectly treating diseases caused by or characterized by the renal fibrosis disease course.
In a specific embodiment, the following polypeptide compounds are involved, the specific sequences of which are:
compound 1 (related to SEQ ID NO: 1):
Thr-His-His-Arg-Pro-Trp-Thr-NH 2
THHRPWT-NH 2
compound 2 (related to SEQ ID NO: 2):
Ala-His-His-Arg-Pro-Trp-Thr-NH 2
AHHRPWT-NH 2
compound 3 (related to SEQ ID NO: 3):
Thr-Ala-His-Arg-Pro-Trp-Thr-NH 2
TAHRPWT-NH 2
compound 4 (related to SEQ ID No. 4):
Thr-His-Ala-Arg-Pro-Trp-Thr-NH 2
THARPWT-NH 2
compound 5 (related to SEQ ID NO: 5):
Thr-His-His-Ala-Pro-Trp-Thr-NH 2
THHAPWT-NH 2
compound 6 (related to SEQ ID NO: 6):
Thr-His-His-Arg-Ala-Trp-Thr-NH 2
THHRAWT-NH 2
compound 7 (related to SEQ ID NO: 7):
Thr-His-His-Arg-Pro-Ala-Thr-NH 2
THHRPAT-NH 2
compound 8 (related to SEQ ID No. 8):
Thr-His-His-Arg-Pro-Trp-Ala-NH 2
THHRPWA-NH 2
compound 9 (related to SEQ ID NO: 9):
His-His-Arg-Pro-Trp-Thr-NH 2
HHRPWT-NH 2
compound 10 (SEQ ID NO: 10):
His-Arg-Pro-Trp-Thr-NH 2
HRPWT-NH 2
compound 11 (related to SEQ ID No. 11):
Thr-Lys-His-Arg-Pro-Trp-Thr-NH 2
TKHRPWT-NH 2
compound 12 (related to SEQ ID NO: 12):
Thr-His-Lys-Arg-Pro-Trp-Thr-NH 2
THKRPWT-NH 2
compound 13 (related to SEQ ID NO: 13):
Thr-His-His-Lys-Pro-Trp-Thr-NH 2
THHKPWT-NH 2
compound 14 (related to SEQ ID No. 14):
Thr-His-His-Arg-Lys-Trp-Thr-NH 2
THHRKWT-NH 2
compound 15 (related to SEQ ID NO: 15):
Ac-Thr-His-His-Arg-Pro-Trp-Thr-NH 2
Ac-THHRPWT-NH 2
compound 16 (related to SEQ ID No. 16):
Ac-Thr-(D-His)-His-Arg-Pro-Trp-Thr-NH 2
Ac-T-(d-H)-HRPWT-NH 2
compound 17 (related to SEQ ID No. 17):
Ac-Thr-His-(D-His)-Arg-Pro-Trp-Thr-NH 2
Ac-TH-(d-H)-RPWT-NH 2
compound 18 (related to SEQ ID No. 18):
Ac-Thr-His-His-(D-Arg)-Pro-Trp-Thr-NH 2
Ac-THH-(d-R)-PWT-NH 2
compound 19 (related to SEQ ID No. 19):
Ac-Thr-His-His-Arg-(D-Pro)-Trp-Thr-NH 2
Ac-THHR-(d-P)-WT-NH 2
compound 20 (related to SEQ ID NO: 20):
compound 21 (related to SEQ ID No. 21):
the abbreviations used in the present invention have the following specific meanings:
thr is threonine, trp is tryptophan, pro is proline, arg is arginine, his is histidine, ala is alanine, lys is lysine, D-His is D-histidine, D-Arg is D-arginine, D-Pro is D-proline, ac is acetyl, DMF is N, N-dimethylformamide, TFA is trifluoroacetic acid, TIS is N, N-triisopropylsilane, DCM is dichloromethane, DMEM is low sugar medium, GAPDH is glyceraldehyde-3-phosphate dehydrogenase, UUO is unilateral ureteral ligation, PBS is phosphate buffer solution.
Drawings
FIG. 1 shows the results of the activity of the polypeptide compounds of example 2 in a tubular epithelial (HK 2) cell model. FIG. 2 is an H & E stained section of the kidney of the mice of example 3.
FIG. 3 is a chart of a section of the kidney of the mice of example 3 stained with Marsonian.
FIG. 4 is a bar graph of the positive areas in the Marsonian staining section of the kidney of the mice of example 3.
FIG. 5 is a graph of a slice of the kidney of the mice of example 3 stained with sirius red.
FIG. 6 is a bar graph of the positive areas in the slice of the kidney of the mice of example 3 in sirius red.
Detailed Description
Embodiments of the present invention will be described in detail below with reference to examples, but it will be understood by those skilled in the art that the following examples are only for illustrating the present invention and should not be construed as limiting the scope of the present invention. The specific conditions are not noted in the examples and are carried out according to conventional conditions or conditions recommended by the manufacturer. Unless otherwise indicated, all reagents or apparatus used are commercially available.
EXAMPLE 1 Synthesis of polypeptide Compounds
For convenience of explanation of the synthesis process of the polypeptide compound of the present invention, the present embodiment is exemplified by the polypeptide compounds 1117 and 20, but the following synthesis process is not limited to the synthesis process of the polypeptide compound of the present invention.
Materials:
all amino acids were purchased from Shanghai Jier Biochemical company and the resin was Rink Amide MBHA (loading=0.36 mmol/g) from West Ann blue. All other reagents were analytically pure, purchased from Shanghai taitant technologies, inc., unless otherwise specified. Phenomenex Luna C18A column (20 mm. Times.250 mm) was prepared for purification of the polypeptide. The high performance liquid chromatograph is a product of Thermofisher company and has a model number of Ultimate 3000. Mass spectrum was measured using an Agilent mass spectrometer model 1260-6120.
1. Synthesis of polypeptide compound 11:
amino acid sequence of polypeptide compound 11:
Thr-Lys-His-Arg-Pro-Trp-Thr-NH 2
1) Coupling of peptide resin:
the following polypeptides were synthesized on a polypeptide synthesizer according to the Fmoc protection strategy:
(1) The first step: amino acid coupling
The preparation method comprises the steps of taking Rink Amide MBHA resin as a carrier, taking 1-hydroxybenzotriazole (3 x) and N, N-diisopropylcarbodiimide (3 x) as coupling agents, taking N, N-dimethylformamide as a solvent, carrying out program reaction, and sequentially carrying out condensation reaction to connect protected amino acids to obtain the amino acid:
the ratio of the amount of 1-hydroxybenzotriazole to N, N-diisopropylcarbodiimide to Fmoc-protected amino acid used in each condensation reaction of the Thr-Lys-His-Arg-Pro-Trp-Thr-Rink Amide MBHA peptide resin is 1:1, deprotection solution is 20% piperidine in DMF. After the coupling, the mixture was contracted with pure methanol and dried under vacuum to obtain 4.2g of a peptide resin.
(2) And a second step of: polypeptide cleavage and deprotection
4.2g peptide resin:
Thr-Lys-His-Arg-Pro-Trp-Thr-Rink Amide MBHA peptide resin is added into a round bottom flask, and under ice bath condition, cutting solution TFA/TIS/H is added 2 45mL of O=95/2.5/2.5 (v/v/v), heating, controlling the temperature of the lysate to 25 ℃, and stirring and reacting for 120 minutes. The mixture was filtered, and the filtrate was poured into glacial diethyl ether with stirring. After complete precipitation, centrifuging, decanting the supernatant, and precipitating with N 2 Drying, and vacuum-pumping overnight to obtain crude polypeptide compound 11 with total weight of 1.2g, wherein the amino acid sequence of polypeptide compound 11 is as follows: thr-Lys-His-Arg-Pro-Trp-Thr-NH 2 。
2) Purified salt transfer
1.2g of the crude product obtained in the second step above was treated with 5.0% acetic acid in acetonitrile: h 2 O=1: 1 (volume ratio) of the solution is dissolved by 20mL of ultrasonic, and after dissolution and clarification, the solution is filtered by a polytetrafluoroethylene film with the thickness of 0.45 mu m to obtain a filtered C5 filtrate. The filtrate was purified by 2 semi-preparative HPLC on a 20mm reverse phase C18 packed 20mm x 250mm column. With 40-60% acetonitrile-0.1% trifluoroacetic acid/H 2 The column was eluted at 19mL/min for 60.0 min with an O gradient, the C5-containing fraction was collected, concentrated to remove acetonitrile and lyophilized from the salt. 145mg of pure product with a HPLC purity of 99.6395% was obtained. The product separated by the liquid chromatography-mass spectrometry analysis, and the m/z+1 value of the ion peak of the protonated molecule is found to be: 933.5, theoretical 933.46.
2. Synthesis of polypeptide compound 17:
amino acid sequence of polypeptide compound 17:
Ac-Thr-His-(D-His)-Arg-Pro-Trp-Thr-NH 2
1) Coupling of peptide resin:
the following polypeptides were synthesized on a polypeptide synthesizer according to the Fmoc protection strategy:
(1) The first step: amino acid coupling
The preparation method comprises the steps of taking Rink Amide MBHA resin as a carrier, taking 1-hydroxybenzotriazole (3 x) and N, N-diisopropylcarbodiimide (3 x) as coupling agents, taking N, N-dimethylformamide as a solvent, carrying out program reaction, and sequentially carrying out condensation reaction to connect protected amino acids to obtain the amino acid:
the ratio of the amount of 1-hydroxybenzotriazole to N, N-diisopropylcarbodiimide to Fmoc-protected amino acid used in each condensation reaction of the Thr-His- (D-His) -Arg-Pro-Trp-Thr-Rink Amide MBHA peptide resin is 1:1, deprotection solution is 20% piperidine in DMF. After the coupling, the mixture was contracted with pure methanol and dried under vacuum to obtain 4.2g of a peptide resin.
(2) And a second step of: n-terminal acetylation of polypeptides
Pyridine and acetic anhydride are taken and dissolved in DMF, and argon is introduced for reaction.
(3) And a third step of: polypeptide cleavage and deprotection
4.2g peptide resin:
Thr-His- (D-His) -Arg-Pro-Trp-Thr-Rink Amide MBHA peptide resin is added into a round bottom flask, and under ice bath condition, cutting solution TFA/TIS/H is added 2 45mL of O=95/2.5/2.5 (v/v/v), heating, controlling the temperature of the lysate to 25 ℃, and stirring and reacting for 120 minutes. The mixture was filtered, and the filtrate was poured into glacial diethyl ether with stirring. Standing for more than 1.0 hr, centrifuging, removing supernatant, and precipitating with N 2 After drying, vacuum drying overnight, 1.2g of crude compound 17 is obtained, wherein the amino acid sequence of polypeptide compound 17 is as follows: ac-Thr-His- (D-His) -Arg-Pro-Trp-Thr-NH 2 。
2) Purified salt transfer
1.2g of the crude product obtained in the third step above was purified with 5.0% acetic acid in acetonitrile: h 2 O=1: 1 (volume ratio) of the solution is dissolved by 20mL of ultrasonic, and after dissolution and clarification, the solution is filtered by a polytetrafluoroethylene film with the thickness of 0.45 mu m to obtain a filtered C5 filtrate. The filtrate was purified by 2 semi-preparative HPLC on a 20mm reverse phase C18 packed 20mm x 250mm column. By using40-60% acetonitrile-0.1% trifluoroacetic acid/H 2 The column was eluted at 19mL/min for 60.0 min with an O gradient, the C5-containing fraction was collected, concentrated to remove acetonitrile and lyophilized from the salt. 145mg of pure product with a HPLC purity of 99.6395% was obtained. The product separated by the liquid chromatography-mass spectrometry analysis, and the m/z+1 value of the ion peak of the protonated molecule is found to be: 975.47, theoretical 975.5.
3. Synthesis of polypeptide compound 20:
the amino acid sequence of polypeptide compound 20 is:
1) The linear peptide main peptide chain is coupled into cyclic peptide:
the following linear peptide resins were synthesized on a polypeptide synthesizer according to the Fmoc protection strategy:
Thr-Lys-His-Arg-Pro-Trp-Thr-gamma Glu (OAll) -Rink Amide MBHA peptide resin
(1) The first step: amino acid coupling
The preparation method comprises the steps of taking Rink Amide MBHA resin as a carrier, taking 1-hydroxybenzotriazole (3 x) and O-benzotriazole-tetramethylurea hexafluorophosphate as coupling agents, taking N, N-dimethylformamide as solvents, carrying out program reaction, and sequentially carrying out condensation reaction to connect protected amino acids to obtain Thr-Lys-His-Arg-Pro-Trp-Thr-gamma Glu (OAll) -Rink Amide MBHA linear peptide resin, wherein the mass ratio of the 1-hydroxybenzotriazole to the O-benzotriazole-tetramethylurea hexafluorophosphate to the N-Fmoc protected amino acid in each condensation reaction is 3:1, deprotection solution is 20% piperidine in DMF.
(2) And a second step of: removal of OAll protecting groups
The obtained product was:
Thr-Lys-His-Arg-Pro-Trp-Thr-gamma Glu (OAll) -Rink Amide MBHA peptide resin is dispersed in DMF solution, palladium tetraphenylphosphine is added, and the mixture is reacted for 12 hours under nitrogen atmosphere, and then washed with DCM (10 mL x 3) and DMF (10 mL x 3) in sequence, and pumped.
(3) And a third step of: head-to-tail amide cyclization
1-hydroxybenzotriazole (3 x) and O-benzotriazole-tetramethyl urea hexafluorophosphate (3 x) are used as coupling agents, and N, N-dimethylformamide is used as a solvent for reaction for 4 hours. After the coupling, the mixture was contracted with pure methanol for 2 times each for 15 minutes, vacuum-dried and weighed to obtain 3.8g of peptide resin.
(4) Fourth step: removal of protecting groups for polypeptide cleavage
3.8g of the resin obtained in (3) was transferred to a round-bottomed flask, and under ice bath, the cleavage liquid TFA/TIS/H was added 2 O=95/2.5/2.5, (V/V/V) 40mL, heating, controlling the temperature of the lysate to 25 ℃, and reacting for 120 minutes. The mixture was filtered, the filter cake was washed 3 times with a small amount of trifluoroacetic acid, and the filtrates were combined. The filtrate was slowly poured into glacial diethyl ether with stirring. Standing for more than 1.0 hour, and completely precipitating. Centrifuging, washing the obtained precipitate with glacial diethyl ether for 3 times to obtain precipitate, and collecting precipitate with N 2 After drying, the mixture was dried under vacuum overnight to give a total of 1.0g of crude compound 20.
2) Purifying and converting salt:
1.0g of the crude product obtained in the fourth step was dissolved by ultrasonic with 30mL of pure water, and after dissolution, the solution was filtered with a polytetrafluoroethylene membrane of 0.45. Mu.m, to obtain a filtered polypeptide compound 20 filtrate. The filtrate was purified by 2 semi-preparative HPLC on a 20mm reverse phase C18 packed 20mm x 250mm column. With 15-35% acetonitrile-0.1% trifluoroacetic acid/H 2 The column was eluted at 19mL/min for 60.0 min with an O gradient, and the fractions containing polypeptide compound 20 were collected, concentrated to remove acetonitrile and lyophilized from the salt. 90mg of pure product with the purity of 99.31% by HPLC is obtained. The product separated by liquid chromatography-mass spectrometry analysis shows that the m/z+1 value of the ionic peak of the protonated molecule is as follows: 907.07, theoretical 907.05.
Polypeptide compounds 1 to 14 were synthesized using the above-described synthesis method of polypeptide compound 11, polypeptide compounds 15 to 19 were synthesized using the above-described synthesis method of polypeptide compound 17, and polypeptide compounds 20 to 21 were synthesized using the above-described synthesis method of polypeptide compound 20, to obtain polypeptide compounds shown in the following table 1:
table 1, structures of polypeptide compounds synthesized in examples of the present invention:
EXAMPLE 2 evaluation of Activity of polypeptide Compounds in a tubular epithelial (HK 2) cell model
The anti-fibrotic activity of polypeptide compounds 1-21 was initially screened using a tgfβ -induced HK2 cell model as an in vitro liver fibrosis cell evaluation model (HK 2 cells were purchased from the national academy of sciences of china, shanghai, china), and the expression of the fibrotic marker Fibronectin (FN) was detected, and the polypeptide compounds 1-21 were subjected to cell incubation with (100. Mu.M) for 24h. The control group was given the same volume of low sugar medium (DMEM) (available from Gibco, usa) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) (available from beijing holo gold biology ltd.) as an internal control, wherein FN protein was a characteristic of fibrosis, and the results are shown in fig. 1.
The results in fig. 1 show that the polypeptide compounds of the invention all have significantly inhibitory improvement activity against FN to a different extent than GAPDH reference. Experimental results also show that: the polypeptide compound of the invention can inhibit the generation of fibrosis at the cell level, and also suggests that: the polypeptide compound of the invention can be potentially used for researching fibrosis symptoms accompanied by organ fibrosis and organ diseases.
EXAMPLE 3 evaluation of the therapeutic Effect of polypeptide Compounds on UFO-induced renal fibrosis in mice
The polypeptide compounds 1-21 are used for treating mice after UFO molding and observing the improvement of renal fibrosis of the mice, and the specific method is as follows:
first, 144C 57BL/6 mice, about 8 weeks, were randomly divided into 24 groups, each 6, provided by the university of middle mountain laboratory animal center, each group being:
normal control group: sham surgery (Sham) +pbs,
model control group: the UUO model + the PBS,
model treatment group: UUO model + benazepril (0.3 mg/kg),
polypeptide compound treatment group:
polypeptide compound 1 group: UUO model + polypeptide compound 1 (1 mg/kg),
polypeptide compound 2 group: UUO model + polypeptide compound 2 (1 mg/kg),
polypeptide compound 3 group: UUO model + polypeptide compound 3 (1 mg/kg),
polypeptide compound 4 group: UUO model + polypeptide compound 4 (1 mg/kg),
polypeptide compound 5 group: UUO model + polypeptide compound 5 (1 mg/kg),
polypeptide compound 6 group: UUO model + polypeptide compound 6 (1 mg/kg),
polypeptide compound 7 group: UUO model + polypeptide compound 7 (1 mg/kg),
polypeptide compound 8 group: UUO model + polypeptide compound 8 (1 mg/kg),
polypeptide compound 9 group: UUO model + polypeptide compound 9 (1 mg/kg),
polypeptide compound 10 group: UUO model + polypeptide compound 10 (1 mg/kg),
polypeptide compound 11 group: UUO model + polypeptide compound 11 (1 mg/kg),
group 12 polypeptide compounds: UUO model + polypeptide compound 12 (1 mg/kg),
polypeptide compound 13 group: UUO model + polypeptide compound 13 (1 mg/kg),
group 14 polypeptide compounds: UUO model + polypeptide compound 14 (1 mg/kg),
polypeptide compound 15 group: UUO model + polypeptide compound 15 (1 mg/kg),
polypeptide compound 16 group: UUO model + polypeptide compound 16 (1 mg/kg),
group 17 polypeptide compounds: UUO model + polypeptide compound 17 (1 mg/kg),
polypeptide compound 18 group: UUO model + polypeptide compound 18 (1 mg/kg),
group 19 polypeptide compounds: UUO model + polypeptide compound 19 (1 mg/kg),
polypeptide compound 20 group: UUO model + polypeptide compound 20 (1 mg/kg),
group 21 polypeptide compounds: UUO model+polypeptide Compound 21 (1 mg/kg).
The UUO model, the Sham operation and the post-operation administration are carried out according to the following steps:
1) UUO model: the C57BL/6 mice were weighed and anesthetized (at a dose of 10. Mu.L/g) by intraperitoneal injection of 5% chloral hydrate (saline); removing abdominal hair of a mouse, fixing the mouse on an operation panel after removing hair, sterilizing the abdomen twice by using iodophor, cutting an incision of approximately 1cm near the left side of the abdomen to expose the kidney, separating out the ureter by using micro forceps, knotting the ureter near the end of the kidney by using a wire, knotting the ureter near the end of the bladder by using a wire, and finally cutting the ureter from the middle of the two knots; 100 mu L of diabody is dripped into the abdomen of the mouse, and finally muscle and skin openings are sequentially sutured.
2) Sham surgery: c57BL/6 mice were weighed and anesthetized (at a dose of 10. Mu.L/g) by intraperitoneal injection of 5% chloral hydrate (saline); removing abdominal hair of a mouse, fixing the mouse on an operation panel after removing hair, sterilizing the abdomen twice by using iodophor, cutting an incision of approximately 1cm near the left side of the abdomen to expose kidneys, separating ureters by using micro forceps, carefully placing internal dirt back into the abdominal cavity, dripping 100 mu L of diabody on the abdomen of the mouse, and finally sequentially suturing muscle and skin openings.
3) Post-operative administration: the following day of surgery, PBS was administered to the normal control group, PBS was administered to the model control group, benazepril was administered at 0.3mg/kg to the model treatment group, and 1mg/kg of the polypeptide compound 1-21 was administered, respectively, once daily at 10 am for two weeks.
Mice were weighed once daily after surgery and recorded, their physiological status was observed, and after 14 days of dosing, the experiment was ended and the mice were fasted the evening the day before sampling. Weighing the mice when taking materials, taking blood from the orbit after anesthesia by using diethyl ether, collecting the blood in a sterilized 1.5mL ep tube (the blood taking amount is about 600 mu L), centrifuging the blood of the mice for 15 minutes at room temperature at 4000rpm after the blood of the mice is completely taken, sucking the supernatant into a new sterilized 1.5mL ep tube, centrifuging the supernatant twice, and storing the final serum at the temperature of-20 ℃ for serological detection; the mice were fixed on the control plate, cut along the midline of the mice, carefully remove the untreated right kidney, place in centrifuge tubes, remove the left kidney, gently strip the kidney membrane, weigh the kidneys, photograph them, then use the surgical blade to cut the kidneys longitudinally along the median sagittal plane, one part of the kidneys was immersed in the newly prepared 10% formalin solution for histopathological examination, the other part of the kidneys was placed in a sterilized 1.5mL eptube-80 ℃ for storage for protein and RNA examination.
The kidneys soaked in the newly prepared 10% formalin solution were subjected to waxing and slicing, and hematoxylin-eosin (H & E) staining, sirius fishy red staining and masson staining were performed respectively. H & E staining: baking and dewaxing; hematoxylin staining for 7 minutes, washing with tap water, differentiating with 1% ethanol hydrochloride for 1s, washing with tap water, eosin staining, washing with tap water, dehydrating and transparentizing, airing, and sealing with gum.
Dyeing sirius scarlet: baking and dewaxing; standing in double distilled water for 5.0 minutes; dyeing the sirius red in the darkroom for 60-80 minutes; rinsing with 0.5% glacial acetic acid for 5s; and (5) dehydrating and transparentizing, sealing the film, and photographing.
Masson staining: baking and dewaxing; mordant dyeing; drop dyeing of azure blue dyeing liquid for 2-3min and washing with water; drop dyeing and water washing of Mayer hematoxylin staining; acid ethanol differentiated solution is differentiated for a plurality of seconds, and is washed by tap water; liquid drop dyeing and distilled water washing of ponceau red and fuchsine dyeing; treating the phosphomolybdic acid solution; dripping aniline blue dye liquor for 5min; treating with weak acid solution for 2min; dehydrating and transparentizing, airing, and sealing with gum.
In the UUO-induced mouse kidney fiber model, kidney performance is characterized by: the renal tubules are severely atrophic, the renal tubule gap is obviously increased, immunocytosis is increased, and the normal renal tissue structure is destroyed.
FIG. 2 is an H & E staining section of the kidney of the mice of this example. As can be seen from the results of fig. 2, the renal tubules of the normal control mice were clear and there was no significant gap; however, compared with the normal control group, the renal tubule of the mice in the model control group is seriously atrophic, the renal tubule gap is obviously increased, the immunocytosis is increased, and the normal renal tissue structure is destroyed; the tissue morphology of mice in the model treatment group and the polypeptide compound treatment group is obviously improved. It can be demonstrated that the polypeptide compound of the present invention can significantly improve tubular atrophy and tubular clearance.
Fig. 3 is a graph of a masson stained section of the kidney of the mouse of example 3, and fig. 4 is a bar graph of the positive area in the masson stained section of the kidney of the mouse of example 3. Masson staining is mainly used for staining of fibres in tissues, where collagen fibres are stained blue and muscle fibres are stained red. From the Masson staining results of the pathological sections of mice, the sections of the mice in the normal control group mainly show red muscle fibers, and a small amount of blue collagen fibers are contained in the sections, so that the collagen fibers in the normal kidneys account for a small part of the total tissues; however, in pathological section staining of model control mice, blue collagen fibers occupy a substantial portion of kidney tissue, almost losing normal kidney morphology; compared with a model control group, the staining result of the tissue section of the mice treated by the polypeptide compound provided by the invention is obviously improved, the blue collagen fiber ratio is obviously reduced, and partial kidney morphology can be seen, and the polypeptide compound provided by the invention has obvious inhibition effect on the collagen fiber. The polypeptide compound of the invention has obvious therapeutic effect on kidney fibrosis.
Fig. 5 is a slice diagram of the dye of sirius red of the kidney of the mouse of example 3, and fig. 6 is a bar chart of the positive areas in the slice diagram of sirius red of the kidney of the mouse of example 3.
As can be seen from the results of fig. 5 and 6, the model control group significantly reduced the degree of renal fibrosis in mice treated with the polypeptide compound of the present invention, thereby demonstrating that the polypeptide compound of the present invention can reduce the degree of renal fibrosis.
From the results of H & E staining, masson staining and sirius scarlet staining, it can be seen that the polypeptide compounds of the present invention are capable of reducing the extent of renal fibrosis and treating renal fibrosis.
In view of the above, the polypeptide compound of the present invention has a good improving or treating effect on renal fibrosis.
The present invention is, of course, capable of other and further embodiments, and its several details are capable of modification in various, obvious respects, all without departing from the spirit and scope of the present invention, as defined by the appended claims.
SEQUENCE LISTING
<110> university of Zhongshan
<120> polypeptide compound for preventing and/or treating renal fibrosis
<130> GD1899-21P126205
<160> 21
<170> PatentIn version 3.5
<210> 1
<211> 7
<212> PRT
<213> artificial sequence
<400> 1
Thr His His Arg Pro Trp Thr
1 5
<210> 2
<211> 7
<212> PRT
<213> artificial sequence
<400> 2
Ala His His Arg Pro Trp Thr
1 5
<210> 3
<211> 7
<212> PRT
<213> artificial sequence
<400> 3
Thr Ala His Arg Pro Trp Thr
1 5
<210> 4
<211> 7
<212> PRT
<213> artificial sequence
<400> 4
Thr His Ala Arg Pro Trp Thr
1 5
<210> 5
<211> 7
<212> PRT
<213> artificial sequence
<400> 5
Thr His His Ala Pro Trp Thr
1 5
<210> 6
<211> 7
<212> PRT
<213> artificial sequence
<400> 6
Thr His His Arg Ala Trp Thr
1 5
<210> 7
<211> 7
<212> PRT
<213> artificial sequence
<400> 7
Thr His His Arg Pro Ala Thr
1 5
<210> 8
<211> 7
<212> PRT
<213> artificial sequence
<400> 8
Thr His His Arg Pro Trp Ala
1 5
<210> 9
<211> 6
<212> PRT
<213> artificial sequence
<400> 9
His His Arg Pro Trp Thr
1 5
<210> 10
<211> 5
<212> PRT
<213> artificial sequence
<400> 10
His Arg Pro Trp Thr
1 5
<210> 11
<211> 7
<212> PRT
<213> artificial sequence
<400> 11
Thr Lys His Arg Pro Trp Thr
1 5
<210> 12
<211> 7
<212> PRT
<213> artificial sequence
<400> 12
Thr His Lys Arg Pro Trp Thr
1 5
<210> 13
<211> 7
<212> PRT
<213> artificial sequence
<400> 13
Thr His His Lys Pro Trp Thr
1 5
<210> 14
<211> 7
<212> PRT
<213> artificial sequence
<400> 14
Thr His His Arg Lys Trp Thr
1 5
<210> 15
<211> 7
<212> PRT
<213> artificial sequence
<220>
<221> MOD_RES
<222> (1)..(1)
<223> ACETYLATION
<400> 15
Thr His His Arg Pro Trp Thr
1 5
<210> 16
<211> 7
<212> PRT
<213> artificial sequence
<220>
<221> MOD_RES
<222> (1)..(1)
<223> ACETYLATION
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa=D-His
<400> 16
Thr Xaa His Arg Pro Trp Thr
1 5
<210> 17
<211> 7
<212> PRT
<213> artificial sequence
<220>
<221> MOD_RES
<222> (1)..(1)
<223> ACETYLATION
<220>
<221> MISC_FEATURE
<222> (3)..(3)
<223> Xaa=D-His
<400> 17
Thr His Xaa Arg Pro Trp Thr
1 5
<210> 18
<211> 7
<212> PRT
<213> artificial sequence
<220>
<221> MOD_RES
<222> (1)..(1)
<223> ACETYLATION
<220>
<221> MISC_FEATURE
<222> (4)..(4)
<223> Xaa=D-Arg
<400> 18
Thr His His Xaa Pro Trp Thr
1 5
<210> 19
<211> 7
<212> PRT
<213> artificial sequence
<220>
<221> MOD_RES
<222> (1)..(1)
<223> ACETYLATION
<220>
<221> MISC_FEATURE
<222> (5)..(5)
<223> Xaa=D-Pro
<400> 19
Thr His His Arg Xaa Trp Thr
1 5
<210> 20
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<212> PRT
<213> artificial sequence
<400> 20
Thr Lys His Arg Pro Trp Thr
1 5
<210> 21
<211> 7
<212> PRT
<213> artificial sequence
<400> 21
Thr His Lys Arg Pro Trp Thr
1 5

Claims (15)

1. A polypeptide compound comprising:
Thr-His-His-Arg-Pro-Trp-Thr-NH 2 (SEQ ID NO: 1) a parent peptide; or alternatively
A polypeptide compound derived from the parent peptide, wherein any of the 1 st to 7 th amino acids in the parent peptide is substituted by Ala, or any of the 2 nd to 5 th amino acids is substituted by Lys or D-type amino acid, or Thr 1 st or/and His 2 nd or N-terminal is/are deleted, or an N-terminal is acetylated.
2. The polypeptide compound of claim 1, wherein the polypeptide compound is a linear peptide or a cyclic peptide formed by the linkage of Thr 1 and Thr 7 in the amino acid sequence by the formation of an amide bond.
3. The polypeptide compound of claim 1, wherein the amino acid sequence of the polypeptide compound is selected from any one of the following after any one of amino acids 1-7 in the parent peptide is substituted with Ala:
compound 2 (SEQ ID NO: 2):
Ala-His-His-Arg-Pro-Trp-Thr-NH 2 ；
compound 3 (SEQ ID NO: 3):
Thr-Ala-His-Arg-Pro-Trp-Thr-NH 2 ；
compound 4 (SEQ ID NO: 4):
Thr-His-Ala-Arg-Pro-Trp-Thr-NH 2 ；
compound 5 (SEQ ID NO: 5):
Thr-His-His-Ala-Pro-Trp-Thr-NH 2 ；
compound 6 (SEQ ID NO: 6):
Thr-His-His-Arg-Ala-Trp-Thr-NH 2 ；
compound 7 (SEQ ID NO: 7):
Thr-His-His-Arg-Pro-Ala-Thr-NH 2 the method comprises the steps of carrying out a first treatment on the surface of the Or (b)
Compound 8 (SEQ ID NO: 8):
Thr-His-His-Arg-Pro-Trp-Ala-NH 2 。
4. the polypeptide compound of claim 1, wherein the parent peptide lacks Thr 1 or/and His 2, and the amino acid sequence of the polypeptide compound is selected from any one of the following:
compound 9 (SEQ ID NO: 9):
His-His-Arg-Pro-Trp-Thr-NH 2 the method comprises the steps of carrying out a first treatment on the surface of the Or (b)
Compound 10 (SEQ ID NO: 10):
His-Arg-Pro-Trp-Thr-NH 2 。
5. the polypeptide compound of claim 1, wherein any of the amino acids at positions 2 to 5 of the parent peptide is substituted with Lys, and wherein the amino acid sequence of the polypeptide compound is selected from any one of the following:
compound 11 (SEQ ID NO: 11):
Thr-Lys-His-Arg-Pro-Trp-Thr-NH 2 ；
compound 12 (SEQ ID NO: 12):
Thr-His-Lys-Arg-Pro-Trp-Thr-NH 2 ；
compound 13 (SEQ ID NO: 13):
Thr-His-His-Lys-Pro-Trp-Thr-NH 2 the method comprises the steps of carrying out a first treatment on the surface of the Or (b)
Compound 14 (SEQ ID NO: 14):
Thr-His-His-Arg-Lys-Trp-Thr-NH 2 。
6. the polypeptide compound of claim 1, wherein the N-terminus of the parent peptide is acetylated, the polypeptide compound having the amino acid sequence:
compound 15 (SEQ ID NO: 15):
Ac-Thr-His-His-Arg-Pro-Trp-Thr-NH 2 。
7. the polypeptide compound of claim 1, wherein the N-terminus of the parent peptide is acetylated and the amino acid His at position 2 is substituted with D-His, the amino acid sequence of the polypeptide compound is:
compound 16 (SEQ ID No. 16):
Ac-Thr-(D-His)-His-Arg-Pro-Trp-Thr-NH 2 。
8. the polypeptide compound of claim 1, wherein the N-terminus of the parent peptide is acetylated and the amino acid His at position 3 is substituted with D-His, the amino acid sequence of the polypeptide compound is:
compound 17 (SEQ ID NO: 17):
Ac-Thr-His-(D-His)-Arg-Pro-Trp-Thr-NH 2 。
9. the polypeptide compound of claim 1, wherein the N-terminus of the parent peptide is acetylated and amino acid Arg at position 4 is substituted with D-Arg, the amino acid sequence of the polypeptide compound being:
compound 18 (SEQ ID NO: 18):
Ac-Thr-His-His-(D-Arg)-Pro-Trp-Thr-NH 2 。
10. the polypeptide compound of claim 1, wherein the N-terminus of the parent peptide is acetylated and amino acid Pro at position 5 is substituted with D-Pro, the amino acid sequence of the polypeptide compound being:
compound 19 (SEQ ID NO: 19):
Ac-Thr-His-His-Arg-(D-Pro)-Trp-Thr-NH 2 。
11. the polypeptide compound of claim 2, wherein the polypeptide compound is a cyclic peptide having an amino acid sequence selected from any one of the following:
compound 20 (SEQ ID NO: 20):
compound 21 (SEQ ID No. 21):
12. use of a polypeptide compound as claimed in any one of claims 1 to 11 in the manufacture of a medicament for the prophylaxis or direct or indirect treatment of renal fibrosis or a condition characterised therein.
13. The use of claim 12, the condition characterized by renal fibrosis comprising: chronic glomerulonephritis, chronic pyelonephritis, obstructive nephropathy, systemic lupus erythematosus nephropathy, hereditary nephropathy, alport syndrome, diabetic nephropathy, hypertensive nephropathy, drug-induced nephropathy, nephropathy caused by hepatitis B or AIDS virus, and kidney transplantation.
14. A pharmaceutical composition comprising a polypeptide compound according to any one of claims 1-11 and at least one pharmaceutically acceptable pharmaceutical carrier and/or adjuvant.
15. The pharmaceutical composition of claim 14, wherein the pharmaceutical composition is in at least one dosage form of a tablet, capsule, dragee, granule, oral solution, syrup, ointments and patches for skin surfaces, aerosol, nasal spray, and sterile solution for injection.
CN202210236822.4A 2022-03-11 2022-03-11 Polypeptide compound for preventing and/or treating renal fibrosis Pending CN116768974A (en)

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Publication number Priority date Publication date Assignee Title
US20140057831A1 (en) * 2011-07-19 2014-02-27 Thrasos Innovation, Inc. Anti-fibrotic peptides and their use in methods for treating diseases and disorders characterized by fibrosis
JP2022520139A (en) * 2018-10-12 2022-03-29 セラダプティブ インク Polypeptides containing β-tricalcium phosphate binding sequence and their use
CN110511266B (en) * 2019-08-07 2022-08-30 南方医科大学南方医院 Small molecule polypeptide and application thereof
EP4021480A4 (en) * 2019-08-30 2023-09-20 The George Washington University Peptides for the treatment of renal disorders
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