WO2021203828A1 - Utilisation d'un inhibiteur dans la préparation de médicaments pour le traitement de la pneumonie due au sars-cov-2 et ses complications - Google Patents

Utilisation d'un inhibiteur dans la préparation de médicaments pour le traitement de la pneumonie due au sars-cov-2 et ses complications Download PDF

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WO2021203828A1
WO2021203828A1 PCT/CN2021/075757 CN2021075757W WO2021203828A1 WO 2021203828 A1 WO2021203828 A1 WO 2021203828A1 CN 2021075757 W CN2021075757 W CN 2021075757W WO 2021203828 A1 WO2021203828 A1 WO 2021203828A1
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sars
protein
cholesterol
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魏从文
张艳红
钟辉
万禄明
高琦
林长青
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中国人民解放军军事科学院军事医学研究院
北京舜景生物医药技术有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4706—4-Aminoquinolines; 8-Aminoquinolines, e.g. chloroquine, primaquine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • 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
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/569—Immunoassay; Biospecific binding assay; Materials therefor for microorganisms, e.g. protozoa, bacteria, viruses
    • G01N33/56983—Viruses
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/92—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving lipids, e.g. cholesterol, lipoproteins, or their receptors
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/52—Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis

Definitions

  • the invention relates to the field of biomedicine, and further relates to the application of an inhibitor in the preparation of a medicine for treating SARS-CoV-2 pneumonia and its complications.
  • SARS-CoV-2 The 2019 novel coronavirus (2019-nCoV, referred to herein as SARS-CoV-2) is the seventh member of the known coronavirus family that can infect humans. It belongs to the ⁇ genus coronavirus of the coronavirus family. This virus genus also includes Atypical pneumonia virus (SARS-CoV) and Middle East respiratory syndrome virus (MERS-CoV).
  • SARS-CoV Atypical pneumonia virus
  • MERS-CoV Middle East respiratory syndrome virus
  • the SARS-CoV-2 genome is an unsegmented single-stranded positive-stranded RNA, which is an irregular nucleic acid part located in the center of the virus particle.
  • SARS-CoV-2 virus particles include four structural proteins: spike protein S, membrane protein E, small molecule membrane protein M, and nucleocapsid protein N.
  • Coronavirus S protein is a baseball-shaped sugar that sticks out of the envelope. Protein belongs to type I membrane fusion protein. During virus maturation, S protein is recognized and cleaved into S1 and S2 fragments by specific proteases.
  • the S1 fragment and the S2 fragment are combined by non-covalent bonds, and they are both embedded in the membrane through the transmembrane region; among them, the S1 fragment contains the N-terminal region and the C-terminal region, which can be used as receptor-binding domains (RBD) .
  • RBD receptor-binding domains
  • SARS-CoV-2S protein binds to its receptor, it induces structural changes in the virus protein, exposing the effective structural domain of the membrane, and mediating the fusion of the virus with the host cell membrane and invading the cell to cause infection.
  • Angiotensin-converting enzyme ACE2 is the main functional receptor of SARS-CoV invading cells, and it is also the main receptor of SARS-CoV-2.
  • Cholesterol is not only an important part of cell membranes, but also a precursor of many biologically active substances with important physiological functions, such as cholic acid, vitamin D and sterol hormones. Therefore, cholesterol homeostasis is critical to maintaining the normal functions of cells and living organisms. Importantly, cholesterol homeostasis at the system level requires coordination among different organizations. Cholesterol is transported in body fluids through lipoproteins. Lipoproteins are classified according to increasing density, including high-density lipoproteins, low-density lipoproteins, etc. Both high-density lipoproteins and low-density lipoproteins are endocytosed through receptors on the cell surface Or the reverse transport of cholesterol.
  • Low-density lipoprotein receptor is a type I transmembrane receptor. LDLR binds to LDL or lipoproteins containing other apolipoproteins ApoB-100 and ApoE, and the lipids it carries are mainly endocytosed into cells by cholesteryl esters. In acidic endosomes, LDL is degraded into amino acids, and cholesterol esters are hydrolyzed by acid esterases into free cholesterol, which enters the free cholesterol pool in the cytoplasm. Therefore, LDLR plays a key role in regulating cholesterol homeostasis and regulating plasma total cholesterol concentration.
  • LDLR Low-density lipoprotein receptor
  • SR-B I is the only lipoprotein receptor that has elucidated the primary structure that can truly mediate the relationship between cells and high-density lipids. Protein, in addition to the liver, it also has a higher concentration in the small intestine, adrenal glands, ovaries, and testes.
  • SR-B I may be located on the plasma membrane called "laces" rich in cholesterol and sphingomyelin micro-regions, these micro-regions are considered to be directly related to cholesterol transport, after SR-B I binds to HDL, it is first selectively mediated HDL cholesterol enters a reversible cholesterol pool in the lacuna, and then cholesterol enters the cholesterol pool in the cell through a certain mechanism.
  • the purpose of the present invention is to provide an inhibitor for the preparation of drugs for the treatment of SARS-CoV-2 pneumonia and its complications.
  • the first aspect of the present invention is to provide the application of an inhibitor in the preparation of a medicine for the treatment of SARS-CoV-2 pneumonia and its complications.
  • the inhibitor has one or more of the following properties: (1) It can reduce the binding of high-density lipoprotein to its receptor; (2) it can reduce the binding of the S protein of SARS-CoV-2 virus to cholesterol.
  • the second aspect of the present invention is to provide a medicine for the treatment of SARS-CoV-2 pneumonia and its complications.
  • the medicine includes an inhibitor, and the inhibitor has one or more of the following properties : (1) It can reduce the binding of high-density lipoprotein to its receptor; (2) It can reduce the binding of the S protein of SARS-CoV-2 virus to cholesterol.
  • the third aspect of the present invention is to provide a method for treating SARS-CoV-2 pneumonia and its complications, including the following steps: administering to a subject suffering from SARS-CoV-2 pneumonia and its complications An effective dose of an inhibitor, which has one or more of the following properties: (1) It can reduce the binding of high-density lipoprotein to its receptor; (2) It can reduce the S protein and cholesterol of the SARS-CoV-2 virus Combine.
  • the treatment of SARS-CoV-2 pneumonia and its complications includes preventing SARS-CoV-2 virus from infecting cells.
  • the prevention here includes the meaning of slowing down and reducing.
  • the ability to reduce the binding of high-density lipoprotein to its receptor includes one or more of the following: (1) reduce the level of high-density lipoprotein receptor; (2) reduce The ability of high-density lipoprotein receptors to bind to high-density lipoproteins;
  • S protein of SARS-CoV-2 virus can reduce the binding of S protein of SARS-CoV-2 virus to cholesterol, including one or more of the following: (1) Reduce the level of S protein of SARS-CoV-2 virus; (2) Reduce S protein of SARS-CoV-2 virus The ability of proteins to bind to cholesterol on high-density lipoproteins.
  • the inhibitor includes one or more selected from the group consisting of small molecule compounds, proteins, polypeptides, and nucleotide sequences.
  • the inhibitor includes one or more selected from the group consisting of: SR-B I protein inhibitor, SBR-I RNAi, SARS-CoV-2 S Competitive peptides for protein and cholesterol binding motifs.
  • the SR-B I protein inhibitor includes: ITX 5061.
  • the sequence of the S protein and cholesterol binding motif of SARS-CoV-2 is selected from one or more of the following: LPPAYTNSFTRGVYYPDKV (SEQ ID NO:1), KVCEFQFCNDPFLGVYYHKNNK (SEQ ID NO: 2), VGYLQPRTFLL (SEQ ID NO: 3), VGGNYNYLYRLFRKSNL (SEQ ID NO: 4), KNTQEVFAQVKQIYKTPPIKDFGGFNFSQIL (SEQ ID NO: 5) and LGKYEQYIKWPWYIWL (SEQ ID NO: 6).
  • the high-density lipoprotein receptor includes a membrane protein receptor; optionally, the SR-B I protein.
  • the drugs for the treatment of SARS-CoV-2 pneumonia and its complications also include other drugs for the treatment of SARS-CoV-2 and its complications, and the treatment of SARS-CoV- 2 and the method of its complications, combined use of drugs for the treatment of SARS-CoV-2 and other drugs for the treatment of SARS-CoV-2 and its complications.
  • the other drugs for the treatment of SARS-CoV-2 pneumonia and its complications are selected from one or more of chloroquine, hydroxychloroquine, and remdesivir.
  • the medicine further includes at least one pharmaceutically acceptable excipient.
  • the use of the drugs is one or more of intravenous injection, intramuscular injection, subcutaneous injection, and oral administration.
  • the fourth aspect of the present invention is to provide a competitive polypeptide of SR-B I protein inhibitor, SBR-I RNAi, SARS-CoV-2 S protein and cholesterol binding motif in the preparation and treatment of SARS-CoV-2 Application of pneumonia and its complications in medicine.
  • the fifth aspect of the present invention is to provide a medicine for the treatment of SARS-CoV-2 pneumonia and its complications, the medicine is selected from one or more of the following: SR-B I protein inhibitor, SBR -I RNAi, SARS-CoV-2 S protein and cholesterol binding motif competitive peptide.
  • the sixth aspect of the present invention is to provide a method for treating SARS-CoV-2 pneumonia and its complications, including the following steps: administering to a subject suffering from SARS-CoV-2 pneumonia and its complications An effective dose of the drug, the drug is selected from one or more of the following: SR-B I protein inhibitor, SBR-I RNAi, SARS-CoV-2 S protein and cholesterol binding motif competitive polypeptide.
  • the SR-B I protein inhibitor includes: ITX 5061.
  • the sequence of the S protein and cholesterol binding motif of SARS-CoV-2 is selected from one or more of the following: LPPAYTNSFTRGVYYPDKV (SEQ ID NO:1), KVCEFQFCNDPFLGVYYHKNNK (SEQ ID NO: 2), VGYLQPRTFLL (SEQ ID NO: 3), VGGNYNYLYRLFRKSNL (SEQ ID NO: 4), KNTQEVFAQVKQIYKTPPIKDFGGFNFSQIL (SEQ ID NO: 5) and LGKYEQYIKWPWYIWL (SEQ ID NO: 6).
  • the seventh aspect of the present invention is to provide an application of a serum cholesterol detection reagent in preparing a detection kit for predicting the prognosis of SARS-CoV-2.
  • the eighth aspect of the present invention is to provide a detection kit for predicting the prognosis of SARS-CoV-2, and the reagent includes a serum cholesterol detection reagent.
  • the inventor found that the concentration of cholesterol will decrease with the severity of the disease, and further discovered that the S protein of SARS-CoV-2 can bind to cholesterol. Therefore, it is speculated that the S protein on the SARS-CoV-2 virus may pass through It binds to cholesterol on high-density lipoprotein, and high-density lipoprotein carries SARS-CoV-2 virus into cells through its reverse transport pathway, resulting in a significant decrease in serum cholesterol and SARS-CoV-2 virus invading cells . On this basis, the inventors used HDL binding protein inhibitors, namely SR-BI protein inhibitors to inhibit SARS-CoV-2 from invading cells.
  • Figure 1A shows the patients infected with SARS-CoV-2 in Example 1 of the present invention, from right to left, according to different disease degrees of Mild, Moderate, Severe, and Critical Classification, the level of TG in the serum.
  • the results showed that although the serum TG level was significantly different between mild and moderate symptoms, it had no correlation with the severity of the disease*, P ⁇ 0.05; **, P ⁇ 0.01; ***, P ⁇ 0.001
  • Figure 1B shows the SARS-CoV-2 infection in Example 1 of the present invention, from right to left according to mild (Mild), moderate (Moderate), severe (Severe), and critical (Critical) different diseases Degree classification, the level of TC in serum. The results showed that the level of free cholesterol in the serum decreased significantly as the disease progressed*, P ⁇ 0.05; **, P ⁇ 0.01; ***, P ⁇ 0.001;
  • Figure 2A shows the patients infected with SARS-CoV-2 in Example 2 of the present invention, from right to left according to the different disease degrees of Mild, Moderate, Severe, and Critical Classification, the level of HDL in the serum.
  • the results showed that the level of HDL in serum decreased significantly with the progress of the disease*, P ⁇ 0.05; **, P ⁇ 0.01; ***, P ⁇ 0.001;
  • Figure 2B shows SARS in Example 2 of the present invention -CoV-2 infected persons are classified according to different disease levels from right to left according to mild (Mild), moderate (Moderate), severe (Severe), and critical (Critical), and the level of serum LDL.
  • the results showed that the level of LDL in serum decreased significantly with the progress of the disease*, P ⁇ 0.05; **, P ⁇ 0.01; ***, P ⁇ 0.001;
  • Figure 3A shows the severely ill patients with SARS-CoV-2 infection in Example 3 of the present invention. They are divided into two groups: Survivors and Non-survivors. Compare the two groups before treatment (Pre-therapy) and treatment. After (Post-therapy) serum TG levels, the results showed that the surviving critically ill patients and the dead critically ill patients, the serum TG levels did not change significantly before and after treatment;
  • Figure 3B shows the SARS-CoV-2 in Example 3 of the present invention Severely infected patients are divided into two groups: Survivors and Non-survivors. The LDL levels in the serum of the two before and after treatment (Pre-therapy) and after treatment (Post-therapy) are compared. The results show that survival is severely ill. There was no significant difference in the level of LDL in the patients' serum before and after treatment. The severely ill patients who died were significantly reduced after treatment*, P ⁇ 0.05; **, P ⁇ 0.01; ***, P ⁇ 0.001;
  • Figure 4A shows the severely ill patients with SARS-CoV-2 infection in Example 4 of the present invention. They are divided into two groups: Survivors and Non-survivors. Compare the two before treatment (Pre-therapy) and treatment. After (Post-therapy) serum TC levels, Figure 4B shows the severely ill patients with SARS-CoV-2 infection in Example 4 of the present invention. They are divided into two groups: Survivors and Non-survivors. Comparison two Before treatment (Pre-therapy) and after treatment (Post-therapy) serum HDL levels. The results showed that compared with before treatment, the levels of TC and HDL in the serum of surviving critically ill patients were significantly increased after treatment, but the opposite was true for dying critically ill patients. Serum TC and HDL levels after treatment were significantly lower than before treatment*, P ⁇ 0.05; **, P ⁇ 0.01; ***, P ⁇ 0.001;
  • FIG. 5A shows the cholesterol binding motif of SARS-CoV-2S protein in Example 5 of the present invention
  • Figure 5B shows the binding and dissociation curve of S protein and cholesterol determined by MST in Example 5 of the present invention.
  • the results show that SARS -The S protein of CoV-2 can bind to cholesterol, with an EC50 of 187.6 ⁇ 120.5nM;
  • Figure 6A shows the effect of ITX5061 on SARS-CoV-2-S pseudovirus invading Hela-ACE2 cells in Example 6 of the present invention.
  • the results show that ITX 5061 can inhibit the invasion of SARS-CoV-2–S, with an EC50 of 0.52. uM ⁇ 0.06;
  • Figure 6B shows the effect of ITX 5061 on the growth of Hela-ACE2 cells in Example 7 of the present invention.
  • the results show that ITX 5061 has no significant effect on cell growth at the indicated concentration.
  • the method for detecting lipids in human serum is as follows: blood is collected overnight after an empty stomach, and the serum is stored in a low-temperature refrigerator at -20°C. Using Beckman Coulter AU5800 automatic biochemical analyzer and Beckman's total cholesterol kit (product number OSR6116), triglyceride detection kit (product number OSR60118), high-density lipoprotein cholesterol detection kit (OSR6187) and low Density Lipoprotein Cholesterol Test Kit (OSR6183), for the detection of cholesterol, triglycerides, HDL and LDL levels in human serum.
  • the detection method of the micro thermal surge experiment is as follows: the recombinant soluble SARS-CoV-2S protein (NCBI Reference Sequence: YP_009724390.1) with His tag and the RED-tris-NTA marker are avoided at room temperature. Light incubate for 30 minutes; prepare 15 concentration gradients of cholesterol in a PCR tube, mix different concentrations of cholesterol with labeled S protein, and incubate for 30 minutes at room temperature.
  • the method for constructing the pseudovirus is as follows: 293T cells are cultured on a 10 cm culture dish to about 70%, and 12 ⁇ g pNL4-3.Luc.ER vector with luciferase reporter gene (purchased from Addgene) ) And 6 ⁇ g of pcDNA3.1-SARS-CoV-2-S vector (we first obtained the S gene of Wuhan-Hu-1 isolate GenBank: MN908947 through total synthesis, and constructed it in the eukaryotic expression vector pcDNA3.1 The pcDNA3.1-SARS-CoV-2-S expression vector) was co-transfected. After 72 hours, the supernatant was collected and purified by centrifugation with a 20% sucrose solution 50000g for 90 minutes to obtain a SARS-CoV-2 pseudovirus.
  • the experimental method of the infection activity of the pseudovirus is as follows: before the pseudovirus infects Hela-ACE2 cells (purchased from Beijing Weitongda Biotechnology Co., Ltd.), HDL (final concentration 300ug/ml) and different concentrations are added to each well
  • the final concentrations of ITX 5061 and ITX 5061 are respectively: 0, 0.0001, 0.001, 0.01, 0.1, 1 and 10uM, and then 5ng pseudovirus per well is used to infect Hela-ACE2 cells in a 96-well plate, each well contains 5000 cells .
  • HDLR inhibitor ITX 5061 purchased from MedChemExpress, catalog number: HY-19900
  • HDL was purchased from Sigma-Aldrich (L8039).
  • the experimental method for detecting the cytotoxicity of ITX 5061 by the MTT method is as follows: collect Hela-ACE2 in a good growth state to prepare a cell suspension, and seed it in a 96-well plate so that the number of cells per well is 5000. After the cells are cultured in a 37°C, 5% CO2 incubator until the cells are fully attached, add ITX 5061 solution, the concentrations of which are: 0, 0.0001, 0.001, 0.01, 0.1, 1 and 10uM, and each group has 6 multiple wells. , And set up blank holes. Place the 96-well plate in an incubator at 37°C and 5% CO2.
  • Example 1 The level of total cholesterol in serum is negatively correlated with the severity of SARS-CoV-2 disease
  • the average level of mmol/L and critical illness is 1.628 ⁇ 1.209 mmol/L; although there is a significant difference in serum triglyceride levels between mild and moderate, there is no difference in levels between moderate, severe and critical Therefore, there is no correlation between triglyceride levels and disease severity (Figure 1A), *, P ⁇ 0.05; **, P ⁇ 0.01; ***, P ⁇ 0.001; 861 patients with SARS-CoV-2 infection
  • the average level of total cholesterol in mild cases was 5.073 ⁇ 1.088mmol/L
  • the average level in moderate cases was 4.674 ⁇ 0.9489mmol/L
  • the average level in severe cases was 4.470 ⁇ 1.143 mmol/L
  • the average level in critical cases was 3.625 ⁇ 1.276 mmol/L.
  • L The level of total cholesterol in serum decreased significantly with the progress of the disease (Figure 1B)*, P ⁇ 0.05; **, P ⁇ 0.01; ***, P ⁇ 0.001.
  • Example 2 The levels of HDL and LDL in serum are negatively correlated with the severity of SARS-CoV-2 disease
  • the average level of critically ill patients is 0.888 ⁇ 0.240mmol/L; the level of HDL in serum decreases significantly as the disease progresses (Figure 2A)*, P ⁇ 0.05; **, P ⁇ 0.01; ***, P ⁇ 0.001;
  • the average level of LDL in 861 patients with SARS-CoV-2 infection was 3.364 ⁇ 0.8137mmol/L in mild cases, 3.165 ⁇ 0.7887mmol/L in moderate cases, and 3.038 ⁇ 0.8916mmol/L in severe cases
  • the average level of L and critical illness is 2.395 ⁇ 0.880 mmol/L; the level of LDL in serum decreases significantly with the progress of the disease (Figure 2B)*, P ⁇ 0.05; **, P ⁇ 0.01; ***, P ⁇ 0.001.
  • Example 5 The S protein of SARS-CoV-2 can bind to cholesterol
  • HDLR inhibitors can inhibit SARS-CoV-2 from invading host cells
  • the non-replicating defective virus HIV (Addgene, USA) as the backbone, it was co-transfected with the pcDNA3.1-SARS-CoV-2-S vector to obtain the SARS-CoV-2 pseudovirus, and conduct the pseudovirus infection activity experiment.
  • the pseudovirus infects Hela-ACE2 cells (purchased from Beijing Weitongda Biotechnology Co., Ltd.), HDL (300ug/ml) and different concentrations of ITX 5061 were added.
  • the concentrations of ITX 5061 were 0, 0.0001, 0.001, 0.01, 0.1, 1 and 10uM, each group set up 6 multiple holes, and set up blank holes.
  • HDLR is one of the co-receptors for SARS-CoV-2 to invade host cells. Therefore, we believe that antagonists targeting HDLR can prevent SARS-CoV-2 from invading host cells, thereby exerting an anti-SARS-CoV-2 virus effect; the levels of total cholesterol and HDL in the serum of infected patients can be used as SARS -A prognostic marker of CoV-2 infection.
  • Example 7 The effect of ITX 5061 on cytotoxicity within the effective concentration range
  • an inhibitor provided by an embodiment of the present invention in the preparation of a medicine for the treatment of SARS-CoV-2 pneumonia and its complications, wherein: the inhibitor has one or more of the following properties: (1) Can reduce High-density lipoprotein binds to its receptor; (2) It can reduce the binding of S protein of SARS-CoV-2 virus to cholesterol.
  • the inventor found that the application of HDL binding protein inhibitor SR-B I protein inhibitor can inhibit SARS-CoV-2 from invading cells.

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Abstract

L'invention concerne l'utilisation d'un inhibiteur dans la préparation de médicaments pour le traitement de la pneumonie due au SARS-CoV-2 et ses complications, l'inhibiteur ayant une ou plusieurs des propriétés suivantes : (1) la réduction de la liaison de la lipoprotéine haute densité à un récepteur de celle-ci ; et (2) la réduction de la liaison de la protéine S du virus SARS-CoV-2 au cholestérol.
PCT/CN2021/075757 2020-04-09 2021-02-07 Utilisation d'un inhibiteur dans la préparation de médicaments pour le traitement de la pneumonie due au sars-cov-2 et ses complications WO2021203828A1 (fr)

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WO2021226520A1 (fr) * 2020-05-08 2021-11-11 Kiromic BioPharma, Inc. Compositions de peptides pour le traitement d'infections pathogènes
CN113144194B (zh) * 2021-02-03 2021-12-14 中国人民解放军军事科学院军事医学研究院 一种GP73抑制剂在制备治疗SARS-CoV-2肺炎及其并发症的药物中的应用
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