WO2022042590A1 - Polypeptides pour réparer des plaies cutanées ou des lésions des muqueuses et applications correspondantes - Google Patents

Polypeptides pour réparer des plaies cutanées ou des lésions des muqueuses et applications correspondantes Download PDF

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WO2022042590A1
WO2022042590A1 PCT/CN2021/114499 CN2021114499W WO2022042590A1 WO 2022042590 A1 WO2022042590 A1 WO 2022042590A1 CN 2021114499 W CN2021114499 W CN 2021114499W WO 2022042590 A1 WO2022042590 A1 WO 2022042590A1
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leu
gly
val
glu
ser
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PCT/CN2021/114499
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耿福能
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四川好医生攀西药业有限责任公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/08—Linear peptides containing only normal peptide links having 12 to 20 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
    • A61K38/06—Tripeptides
    • 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
    • A61K38/07—Tetrapeptides
    • 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
    • A61K38/08—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
    • A61K38/10—Peptides having 12 to 20 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/64—Proteins; Peptides; Derivatives or degradation products thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0802—Tripeptides with the first amino acid being neutral
    • C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/10—Tetrapeptides
    • C07K5/1002—Tetrapeptides with the first amino acid being neutral
    • C07K5/1005—Tetrapeptides with the first amino acid being neutral and aliphatic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/06—Linear peptides containing only normal peptide links 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

Definitions

  • the present invention relates to a novel polypeptide for repairing skin wound or mucosal injury and its application.
  • the polypeptide of the present invention has no homology with known polypeptides and has the effect of repairing mucosal injury or skin injury.
  • Skin trauma and/or mucosal damage are common pathological features of many diseases.
  • Skin trauma or skin injury refers to the damage of normal skin (tissue) caused by external injury factors such as surgery, external force, heat, current, chemical substances, low temperature and internal factors in the body such as local blood supply disorders.
  • Skin damage is often accompanied by disruption of skin integrity and loss of a certain amount of normal tissue, while at the same time, the normal function of the skin is impaired. Also called a wound or trauma.
  • protein/polypeptide drugs including basic fibroblast growth factor, epidermal growth factor, platelet growth factor, granulocyte-macrophage colony-stimulating factor and growth hormone that have obvious effects on wound repair, skin care, anti-wrinkle and anti-aging, but these
  • the long amino acid sequence of protein/polypeptide drugs leads to the disadvantages of high preparation cost and poor stability, so their application is limited to a certain extent.
  • Epidermal growth factor is a polypeptide consisting of 53 amino acid residues, which is widely present in various tissues, organs and body fluids. It can promote the proliferation of epithelial cells and protect the skin. Epidermal growth factor mainly promotes the proliferation and growth of skin tissue cells, so that new cells can replace aging cells, so as to play anti-aging and skin care and health care functions. Epidermal growth factor has been reported to have the effect of repairing wounds. When skin wounds need to be disinfected and debridement, disinfectants containing iodine or hydrogen peroxide will be applied. EGF is unstable under these conditions. Growth factors are related to gastrointestinal healing (J. Surgical Res. 2014; 17:202-210), but when EGF is orally administered orally, it will degrade after entering the body, and the therapeutic effect cannot be achieved in the experiment.
  • Human mucosa refers to the inner layer of cavities or cystic muscular organs such as respiratory system, digestive system, genitourinary system, etc. It is the second largest barrier of human body after skin, including oral cavity, pharynx, trachea, esophagus, stomach and intestines. , vagina, bladder, etc.
  • the wall or cyst wall of these organs has a common stratification law, and has the characteristics of adapting to its function, and its embryonic origin, tissue structure, pathological process, clinical manifestations, prognosis, etc. have the same characteristics.
  • Chronic gastritis is a chronic inflammation of the gastric mucosa, which is a common and frequently-occurring disease in the department of gastroenterology. Atrophic lesions of the glands are called chronic gastritis.
  • the damage of mucosal tissue can clinically lead to gastrointestinal diseases such as chronic gastritis and peptic ulcer.
  • the repair of mucosal epithelium has two different mechanisms: restitution and regeneration (Cur. Med. Chem., 2008, 15, 3133-3144): repair or recovery generally begins within minutes after injury , rapid repair of superficial lesions through cell migration; regeneration is continuous regeneration through the differentiation and proliferation of stem and progenitor cells for days to months.
  • the treatment drugs for acute and chronic gastritis and peptic ulcer mainly include gastric acid inhibitors, gastric mucosal protective agents, antibiotics and other small molecular compounds.
  • the therapeutic effect is limited, and it protects and promotes the repair of damaged mucosa. This is the treatment of acute and chronic gastritis and peptic ulcer.
  • gastric mucosal protective agents mainly work by protecting the damaged mucosa and have a tissue repair effect.
  • the therapeutic effect is limited, the efficacy is poor, the course of treatment is long, and the recurrence rate is high. It is very necessary to have drugs for better protection and tissue repair of mucosal mucosa.
  • Peptide drugs have the characteristics of strong biological activity and high safety. It is of great significance to screen, discover and develop peptide drugs that can treat skin damage and can treat mucosal damage by oral administration. .
  • the purpose of the present invention is to provide a new type of polypeptide.
  • the present invention provides a compound of formula (I), or a physiologically compatible salt thereof, wherein said compound of formula (I) is as follows:
  • X aa1 is Pro or missing
  • X aa2 is Val or missing
  • X aa3 is Lys, Pro or missing
  • X aa4 is Leu, Val, Ala or missing
  • X aa5 is Lys, Arg or missing
  • X aa6 is Ser, Thr, Ala or missing
  • X aa7 is Lys, Arg or missing
  • X aa8 is Leu, Val, Ala, Ile or missing
  • X aa9 is Gly, Pro, Ala or missing
  • X aa10 is Asp, Glu, Asn, Val or missing;
  • X aa11 is Leu, Val, Ala, Ile, Pro or missing;
  • X aa12 is Leu, Val, Ala or missing
  • X aa13 is Pro, Ala, Gly, Val or missing;
  • X aa14 is Gly, Ala or missing
  • X aa15 is Gly, Ala or missing
  • X aa16 is Glu, Gln, Asp or missing
  • X aa17 is Glu, Asp, Gln or missing.
  • X aa1 is deleted.
  • X aa2 is deleted.
  • both X aa1 and X aa2 are deleted.
  • X aa4 -X aa5 -X aa6-X aa7 is Leu-Lys-Ser-Lys.
  • X aa4 -X aa5 -X aa6 -X aa7 -X aa8 is Leu-Lys-Ser-Lys-Leu.
  • X aa4 -X aa5 -X aa6 -X aa7 -X aa8 is Lys-Ser-Lys-Leu, wherein X aa4 is deleted.
  • X aa9 -X aa10 are Gly-Asp. In one embodiment, X aa9 -X aa10 -X aa11 is Gly-Asp-Leu. In one embodiment, X aa9 -X aa10 -X aa11 is Gly-Asp-Val, Gly-Asp-Ala, or Gly-Asp-Ile.
  • X aa12 is Leu, Val or Ala, preferably Leu.
  • X aa13 - X aa14 are Pro-Gly. In one embodiment, X aa13 -X aa14 -X aa15 is Pro-Gly-Gly. In one embodiment, X aa13- X aa14 -X aa15 -X aa16 -X aa17 is Pro-Gly-Gly-Glu-Glu.
  • X aa13- X aa14 -X aa15 -X aa16 -X aa17 is Ala-Gly-Gly-Glu-Glu, Gly-Gly-Gly-Glu-Glu, Pro-Gly-Gly-Glu-Asp , Pro-Gly-Gly-Gln-Glu, Pro-Gly-Gly-Glu-Gln, Pro-Gly-Gly-Asp-Asp, Pro-Ala-Ala-Asp-Asp, Val-Gly-Gly-Glu-Glu or Pro-Ala-Ala-Gln-Gln.
  • the present invention provides a method of repairing a skin wound, the method comprising contacting the skin wound with a compound of the invention or a physiologically compatible salt thereof.
  • the skin wound is associated with, but not limited to, epidermal inflammation, mechanical and surgical wounds, burns and scalds, ulcers, fistulas, bedsores, and skin lesions caused by chemoradiotherapy.
  • the skin wound refers to the damage to normal skin caused by external injury factors such as surgery, external force, heat, current, chemical substances, low temperature, and internal factors in the body such as local blood supply disorders. .
  • the skin wound is often accompanied by disruption of skin integrity and loss of a certain amount of normal tissue.
  • the skin wound comprises impairment of the normal function of the skin.
  • the present invention provides a method of promoting the proliferation of HaCAT cells, the method comprising contacting the cells with a compound of the present invention or a physiologically compatible salt thereof.
  • the present invention provides a method of repairing mucosal damage, the method comprising administering to a subject a compound of the present invention or a physiologically compatible salt thereof or making the mucosal damage a compound of the present invention or a physiologically compatible salt thereof salt exposure.
  • the mucosal damage is mucosal damage in the lumen of the digestive system, respiratory system and the like.
  • Digestive system mucosal damage is related to oral cavity, esophagus, and gastrointestinal diseases, and the oral diseases include oral ulcers, stomatitis, gingivitis, periodontitis, etc.; the esophageal diseases include esophagitis, esophageal ulcers, etc.; the gastrointestinal diseases Including chronic gastritis, chronic atrophic gastritis, acute gastritis, gastroduodenal ulcer, functional gastrointestinal diseases, dyspepsia, precancerous lesions, digestive system tumors, gastrointestinal bleeding, gastroesophageal reflux disease, acute and chronic Enteritis, ulcerative colitis, Crohn's disease, and mucosal damage from chemoradiation, but not limited thereto.
  • the digestive tract mucosa includes gastric mucosa and intestinal mucosa.
  • the mucosal damage is gastric mucosal damage caused by irritating substances or drugs, stress states.
  • the irritant substances are such as hydrochloric acid, ethanol or alcohol, and the drugs are such as non-steroidal anti-inflammatory drugs aspirin or indomethacin.
  • the present invention provides a method of preventing, alleviating or treating a disease of the digestive tract or eliminating inflammatory edema, the method comprising administering to a subject a compound of the present invention or a physiologically compatible salt thereof.
  • the gastrointestinal diseases include oral cavity, esophagus, and gastrointestinal diseases, and the oral diseases include oral ulcers, stomatitis, gingivitis, periodontitis, etc.; the esophageal diseases include esophagitis, esophageal ulcers, etc.; the gastrointestinal diseases include Diseases include chronic gastritis, chronic atrophic gastritis, acute gastritis, gastroduodenal ulcer, functional gastrointestinal disease, dyspepsia, precancerous lesions, digestive system tumors, gastrointestinal bleeding, gastroesophageal reflux disease, acute Chronic enteritis, ulcerative colitis, Crohn's disease and mucosal damage from chemoradiation; but not limited thereto.
  • the prevention, alleviation or treatment of the digestive tract disease is performed by modulating stem cell proliferation and differentiation.
  • the compounds of the present invention or their physiologically compatible salts play a protective effect on gastrointestinal mucosa such as gastric mucosa or intestinal mucosa, or repair the damage of digestive tract mucosa such as gastric mucosa or intestinal mucosa, thereby preventing and reducing the damage to the digestive tract mucosa. Or the role of the treatment of gastrointestinal diseases.
  • the present invention provides a method of repairing a mucosal or skin wound comprising administering to a subject a compound of the present invention or a physiologically compatible salt thereof.
  • the compound of the present invention or a physiologically compatible salt thereof is administered orally, by injection, subcutaneously, or the like.
  • the present invention provides a pharmaceutical, food, health care product or cosmetic, daily necessities composition
  • a pharmaceutical, food, health care product or cosmetic, daily necessities composition comprising the compound of the present invention or a physiologically compatible salt thereof and a physiologically acceptable carrier.
  • the physiologically acceptable carrier includes a pharmaceutically acceptable carrier or a cosmetically acceptable carrier.
  • the pharmaceutical food, health care product or cosmetic, daily necessities composition can be prepared according to conventional techniques of formulation or cosmetics, including mixing the compound of the present invention as an active ingredient with a carrier, and preparing the desired dosage form according to conventional techniques.
  • the composition of the present invention can be formulated into oral administration preparations, mucosal administration preparations, injection preparations, inhalation preparations and external preparations as required.
  • the polypeptide of the present invention has no homology with known polypeptides, which is convenient for artificial polypeptide synthesis to obtain a high-purity polypeptide.
  • the polypeptide of the present invention only consists of at most 21 amino acid residues, and the polypeptide of the present invention is orally administered After administration, it can significantly eliminate inflammation and edema, promote the repair of gastrointestinal mucosal damage, and reduce the pathological development of gastrointestinal diseases such as acute and chronic gastritis and peptic ulcer; it has the functions of promoting skin wound repair, shortening wound healing time, and regulating immune function. Oral administration can also work.
  • the polypeptide of the present invention when used for skin wounds on the surface of the body, it can work even after being sterilized by iodine preparations or hydrogen peroxide. effect.
  • physiologically compatible salts refers to salt forms that are physiologically compatible (ie, pharmacologically acceptable) and that are substantially non-toxic to the individual to which the compounds of the present invention will be administered.
  • Physiologically compatible salts of the compounds of the present invention include conventional and stoichiometric acid or base addition salts formed from suitable, non-toxic, organic or inorganic acids or inorganic bases.
  • skin damage in this application includes, in addition to skin breaks, burns, scalds, etc., skin damages repaired for cosmetic purposes such as wrinkles (e.g., wrinkles caused by ultraviolet radiation), skin lines, cracks, bumps, Large pores (eg associated with adnexal structures such as sweat ducts, sebaceous glands, or hair follicles), or uneven or rough, skin loss of elasticity (loss and/or inactivation of functional skin elastin), sagging (including eye and jaw puffiness), Loss of skin firmness, loss of skin firmness, loss of skin's ability to recover from deformation, discoloration (including dark circles), blemishes, sallow complexion, hyperpigmented skin areas such as age spots and freckles, keratin, abnormal
  • Polypeptide compounds are synthesized by conventional solid-phase synthesis methods, and go through multiple cycles of resin swelling, substitution, deprotection, washing, amino acid dissolution, amino acid activation and condensation, washing, re-deprotection, and finally cleavage and side chain deprotection.
  • Polypeptide compounds are synthesized by conventional solid-phase synthesis methods, and go through multiple cycles of resin swelling, substitution, deprotection, washing, amino acid dissolution, amino acid activation and condensation, washing, re-deprotection, and finally cleavage and side chain deprotection.
  • the reaction scheme for solid-phase synthesis is shown below:
  • 2-Chlorotrityl Chloride resin DMF N,N-Dimethylformamide DCM Dichloromethane PIP piperidine HOBt 1-Hydroxybenzotriazole DIPEA N,N-Diisopropylethylamine Methanol methanol Tert-Butyl methyl ether Methyl tert-butyl ether TFA Trifluoroacetate TIS Triisopropylsilane DIC N,N'-Diisopropylcarbodiimide Ethanol Ethanol Aa amino acid
  • Fmoc-Glu(OtBu)-resin According to resin, Fmoc-Glu(OtBu)-OH ⁇ H 2 O, DIPEA, Fmoc-Glu(OtBu)- OH ⁇ H 2 O and DIPEA were added to the synthesis tube. Bubble and shake with N2 at room temperature for 1 to 3 hours, and then drain the resin; then wash with dimethylformamide (DMF) for 5 times, 100 ml/time, and drain the resin.
  • DMF dimethylformamide
  • Amino acid connection Pour the activated protected amino acid solution into the reactor, and add an appropriate amount of DCM to clean the utensils. N2 bubbling reaction at room temperature for 1 to 3 hours, the ninhydrin method detects whether the amino acid connection is complete, if complete, drain. The resin was washed 5 times with DMF, 100ml/time, 3min/time, and drained. The consumption of each amino acid and condensing agent is shown in Table 2.
  • steps (4) and (5) are repeated to extend the peptide chain according to the amino acid sequence until the coupling of the last amino acid is completed.
  • UV detection wavelength 220nm
  • UV detection wavelength 220nm
  • the double-charged peak indicates that the target molecule binds 2 protons, and the triple-charged peak indicates that the target molecule binds 3 protons; N/A means that it is difficult to weigh, excluding the actual weight.
  • HaCaT cells human immortalized keratinocytes
  • + represents the proliferation rate of 120-150%
  • ++ represents the proliferation rate of 150-200%
  • +++ represents the proliferation rate of 200-250%
  • ++++ represents the proliferation rate
  • the proliferation rate is 250 to 300%
  • SPF grade SD rats (body weight 180-230 g) were kept in clean and sterilized cages, given water, feed and bedding at regular intervals every day, keeping the raising temperature at 22°C and humidity at 55%-65%, and rearing for a week to make them adapt to the environment .
  • rats were successfully anesthetized by intraperitoneal injection of 3% sodium pentobarbital, the hair at the edge of the wound was cut off 1 cm, and the wound area was first disinfected with iodophor, and then 75% alcohol was used to locally disinfect the wound area.
  • a 1.5cm ⁇ 1.5cm (that is, a diameter of 1.5cm) circular full-thickness skin incision was made with the spine as the midline on the 4cm proximal side of the neck, deep to the muscle layer.
  • the surrounding skin was fixed with a rubber ring to form an animal model of acute mechanical injury.
  • the wounds of the rats were exposed, and they were kept in a single cage.
  • the model control group physiological saline
  • the EGF control group trade name: Jinin peptide
  • the compound 1 treatment group high and low doses, 2 and 0.4 mg/mL, respectively
  • debridement with iodophor was used first, and then the wound surface was rinsed with sterile saline and wiped dry. Local administration was administered once a day, and 35 ⁇ L was dripped onto the wound surface for 14+ days.
  • Body weight monitoring and wound surface observation were performed once a day. The result is as follows:
  • Example 4 The repairing effect of the new polypeptide compound 1 on skin wounds in mice
  • mice 60 8-10 week old male Kunming mice (purchased from Beijing Speifu Biotechnology Co., Ltd.) were selected and raised in separate cages and fed freely, and stopped eating one day before the test. The mice were anesthetized by intraperitoneal injection of 0.2 ml of 1% pentobarbital sodium, the back was sheared, and a 0.5cm*0.5cm square wound was opened symmetrically up and down the epidermis of the spine. .
  • the test results show that the new polypeptide compound 1 can significantly promote the healing of skin wounds in mice, which has a significant difference compared with the control group, and is better than Kangfuxin Liquid.
  • Example 5 Anti-ulcer effect of some polypeptide samples obtained in Example 1 on ethanol-induced gastric ulcer model in mice
  • mice were randomly divided into 5 groups: 5 mice in the blank group, 10 mice in the model group, 10 mice in the teprenone group, and 10 mice in each polypeptide compound administration group.
  • the prednone group was given 160 mg/kg by intragastric administration
  • the polypeptide administration group was given different test samples by intragastric administration at 0.2 mg/kg.
  • Absolute ethanol was used for modeling, and the animals were sacrificed by de-neck method after 1 h, the gastric cardia was ligated and the pylorus was clipped, and the whole stomach was extracted.
  • Ulcer index calculation method If the length of the cord-like injury is greater than 1mm, the length is measured, and each millimeter is counted as 1 point; if the width is greater than 1mm, the score will be doubled according to the number of millimeters of the width; if the length is less than 1mm, 0.5 points will be scored. Addition gives the animal's ulcer index.
  • Ulcer inhibition rate % (Ulcer index in model group-Ulcer index in drug administration group)/Ulcer index in model group ⁇ 100%;
  • Relative ulcer inhibition rate (Ulcer inhibition rate of test compound)/(Ulcer inhibition rate of compound 1).
  • the anti-ulcer effect of the series of compounds has been completed by several batches of tests, and the relative activity is expressed as the relative ulcer inhibition rate for the convenience of comparison.
  • the ulcer index higher than the model group is negative, indicated as "-"; the ulcer index lower than the model group is positive, indicated as "+”.
  • Compound 1 was used as the control group for each batch of experiments, and the relative ulcer inhibition rate of compound 1 was set to 1, denoted as "+++";
  • the relative ulcer inhibition rate was 0.9-1.20, expressed as "+++";
  • the relative ulcer inhibition rate was 0.6–0.9, denoted as "++";
  • the relative ulcer inhibition rate was 0.3–0.6, denoted as "+";
  • Relative ulcer inhibition rate ⁇ 0.3 expressed as "/" (very low activity).
  • Test method 75 male SD rats weighing 180-210 g (purchased from Beijing Speifu Biotechnology Co., Ltd.) were selected, and after 1 week of adaptive feeding in separate cages, they were randomly divided into blank group, model group, and sucralfate group (1 g /kg, positive drug group), compound 1 low dose group (1.5 mg/kg) and high dose group (3.0 mg/kg).
  • the administration group was given intragastric administration.
  • One day before the modeling the rats were fasted and watered. Except for the control group, the model was established by the bound water immersion method.
  • the rats in each group were fixed on the rat board and immersed in a constant temperature water tank with a temperature of 20 °C for 8 hours. The rat xiphoid process is flush.
  • the ulcer index was calculated according to the Guth standard: 1 point for spot bleeding, 2 points for linear bleeding length ⁇ 1 mm, 4 points for 2-4 mm, 5 points for > 4 mm, and 2 points for width > 1 mm. The results are shown in Table 8.
  • test results show that the new polypeptide compound 1 has obvious protective effect on stress gastric ulcer in rats, and there is a significant difference compared with the model group, and its protective effect is better than that of the positive drug sucralfate.
  • Example 7 Gastric and intestinal stability test of some polypeptide samples and stability after disinfectant treatment
  • W stands for artificial gastric juice
  • X stands for artificial intestinal fluid
  • I stands for povidone-iodine solution
  • O stands for hydrogen peroxide solution
  • results As shown in Table 9, the samples of the test compounds 1, 2, 3, 5, 18, and 19 were 100% retained in the povidone-iodine solution (I) and the hydrogen peroxide solution (O), indicating that they can be combined with Disinfectants are used together and are very stable after disinfection; compounds 5, 18, and 19 are also stable to artificial gastric juice (W) and artificial intestinal juice (X), and compounds 2 and 3 are also stable to artificial intestinal juice (X). There is no retention in gastric juice and intestinal juice, indicating that it is not stable in gastric juice and intestinal juice, and povidone-iodine solution and hydrogen peroxide solution will be destroyed after applying EGF for external use.

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Abstract

La présente invention concerne de nouveaux polypeptides pour réparer des plaies cutanées ou des lésions des muqueuses et des applications correspondantes. Une série de polypeptides de la présente invention sont non homologues à des polypeptides connus et ont un effet de régulation de la prolifération et de la différenciation cellulaires ; les polypeptides sont utilisés pour réparer des lésions des muqueuses ou des plaies cutanées et sont utilisés pour prévenir, soulager ou traiter des maladies gastro-intestinales telles que la gastrite et l'ulcère gastrique.
PCT/CN2021/114499 2020-08-26 2021-08-25 Polypeptides pour réparer des plaies cutanées ou des lésions des muqueuses et applications correspondantes WO2022042590A1 (fr)

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