WO2021218988A1 - Agoniste de prdx1 et son utilisation - Google Patents

Agoniste de prdx1 et son utilisation Download PDF

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WO2021218988A1
WO2021218988A1 PCT/CN2021/090477 CN2021090477W WO2021218988A1 WO 2021218988 A1 WO2021218988 A1 WO 2021218988A1 CN 2021090477 W CN2021090477 W CN 2021090477W WO 2021218988 A1 WO2021218988 A1 WO 2021218988A1
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hydrogen
prdx1
alkyl
fluorine
selective agonist
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PCT/CN2021/090477
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English (en)
Chinese (zh)
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罗成
张豪
徐珩
蒋华良
陈凯先
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中国科学院上海药物研究所
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Publication of WO2021218988A1 publication Critical patent/WO2021218988A1/fr

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    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/32—Oxygen atoms
    • C07D209/34—Oxygen atoms in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • This application relates to the field of biomedicine, in particular to a PRDX1 agonist and its use.
  • Fluvastatin sodium is the first fully synthesized HMG-CoA reductase inhibitor. It was approved for marketing in 1994 for lowering plasma cholesterol levels and preventing cardiovascular diseases. Its active ingredient, fluvastatin, inhibits HMG-CoA (HMG-CoA) reductase through competition, prevents the conversion of HMG-CoA into mevalonate, and blocks the rate-limiting step of cholesterol biosynthesis.
  • Hydroperoxidase 1 belongs to the family of hydroperoxidase (PRDX). Hydroperoxidase family proteins are a class of antioxidant proteins that are widespread in mammalian cells. In general, peroxides in cells oxidize the reactive cysteine conserved in the active center of PRDX protein to make PRDX protein change from a reduced state to an oxidized state. PRDX family proteins perform biological functions by switching between the reduced state and the oxidized state. But at present, PRDX1 has not yet found a high-activity small molecule agonist.
  • this application determines the activity of fluvastatin or its salt to activate PRDX1 through an activity screening system that directly targets hydroperoxidase 1 (PRDX1). And through the molecular level small molecule-macromolecule combination and crystallization experiments to confirm the on-target effect of fluvastatin or its salt. Specifically, this application has discovered that fluvastatin or its salt has an activating effect on the enzymatic activity of PRDX1.
  • the method of optimizing the stability of PRDX1 protein by molecular dynamics simulation is the first to obtain the crystal structure of the complex of fluvastatin or its salt and PRDX1 protein, and analyze the binding mode of fluvastatin or its salt to PRDX1 in detail, and use molecular level binding SPR and MST were used to detect the affinity of fluvastatin or its salt to PRDX1.
  • the present application provides a peroxidase reductase 1 (PRDX1) selective agonist, which comprises a compound capable of activating the activity of the PRDX1 enzyme, and the compound and one or more selected from the group consisting of PRDX1 Amino acid residue-specific interactions: amino acid residues 78, 79 and 108-124 of SEQ ID NO:1.
  • PRDX1 peroxidase reductase 1
  • the compound specifically binds to the one or more amino acid residues of the PRDX1.
  • the one or more amino acid residues comprise the 110th amino acid of SEQ ID NO:1.
  • the compound can form a hydrogen bond with the side chain of the 110th amino acid of SEQ ID NO:1.
  • the compound is capable of forming a water bridge hydrogen bond network between the 78th amino acid residue and/or the 79th amino acid residue of the SEQ ID NO:1 and the PRDX1.
  • the compound is capable of increasing the superoxidation of PRDX1 in H 2 O 2 treatment compared to treatment with H 2 O 2 alone.
  • the compound can inhibit the increase in ROS levels caused by H 2 O 2 stimulation.
  • the compound does not substantially activate the enzymatic activity of PRDX2, PRDX3, PRDX4, PRDX5, and/or PRDX6.
  • the compound comprises fluvastatin, its prodrugs, its metabolites or derivatives, or its pharmaceutically acceptable salts or esters.
  • the compound comprises a compound of formula I or a pharmaceutically acceptable salt or ester thereof:
  • R and R0 is And the other one is a primary or secondary C 1 -C 6 alkyl, C 1 -C 3 cycloalkyl or phenyl -(CH 2 )m- which does not contain asymmetric carbon atoms, where R4 is hydrogen, and C 1 -C 3 alkyl, n-butyl, isobutyl, tert-butyl, C 1 -C 3 alkoxy, n-butoxy, isobutoxy, trifluoromethyl, fluorine, chlorine, phenoxy or benzyloxy base,
  • R 5 is hydrogen, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, trifluoromethyl, fluorine, chlorine, phenoxy or benzyloxy,
  • R 5a is hydrogen, C 1 -C 2 alkyl, C 1 -C 2 alkoxy, fluorine or chlorine, and
  • n 1, 2 or 3 when R 4 is hydrogen, R 5 and R 5a are both hydrogen, when R 5 is hydrogen, R 5a is hydrogen, one of R 4 and R 5 is trifluoromethyl, R 4 At most one of and R 5 is a phenoxy group, and at most one of R 4 and R 5 is a benzyloxy group,
  • R 2 is hydrogen, C 1 -C 3 alkyl, n-butyl, isobutyl, tert-butyl, C 3 -C 6 cycloalkyl, C 1 -C 3 alkoxy, n-butoxy, isobutyl Oxy, trifluoromethyl, fluorine, chlorine, phenoxy or benzyloxy,
  • R 3 is hydrogen, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, trifluoromethyl, fluorine, chlorine, phenoxy or benzyloxy, when R 2 is hydrogen, R 3 is hydrogen , At most one of R 2 and R 3 is trifluoromethyl, at most one of R 2 and R 3 is phenoxy, and at most one of R 2 and R 3 is benzyloxy,
  • R 6 is hydrogen or C 1 -C 3 alkyl
  • R 7 is hydrogen, C 1 -C 3 alkyl, n-butyl, isobutyl, tert-butyl, benzyl or M, where M is a cation.
  • the M is a pharmaceutically acceptable cation.
  • the compound comprises a compound of formula II or a pharmaceutically acceptable salt or ester thereof:
  • R 1 is a primary or secondary C 1 -C 6 alkyl group that does not contain asymmetric carbon atoms, C 3 -C 6 cycloalkyl group or phenyl -(CH 2 )m-, where m is 1, 2 or 3,
  • R 2 is hydrogen, C 1 -C 3 alkyl, n-butyl, isobutyl, tert-butyl, C 3 -C 3 cycloalkyl, C 1 -C 3 alkoxy, n-butoxy, isobutyl Oxy, trifluoromethyl, fluorine, chlorine, phenoxy or benzyloxy,
  • R 3 is hydrogen, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, trifluoromethyl, fluorine, chlorine, phenoxy or benzyloxy.
  • R 2 is hydrogen
  • R 3 is hydrogen
  • At most one of R 2 and R 3 is trifluoromethyl
  • at most one of R 2 and R 3 is phenoxy
  • at most one of R 2 and R 3 is benzyloxy
  • R 4 is hydrogen, C 1 -C 3 alkyl, n-butyl, isobutyl, tert-butyl, C 1 -C 3 alkoxy, n-butoxy, isobutoxy, trifluoromethyl, fluorine , Chloro, phenoxy or benzyloxy,
  • R 5 is hydrogen, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, trifluoromethyl, fluorine, chlorine, phenoxy or benzyloxy,
  • R 5a is hydrogen, C 1 -C 2 alkyl, C 1 -C 2 alkoxy, fluorine or chlorine, when R 4 is hydrogen, R 5 and R 5a are both hydrogen, and when R 5 is hydrogen, R 5a is Hydrogen, at most one of R 4 and R 5 is trifluoromethyl, at most one of R 4 and R 5 is phenoxy, and at most one of R 4 and R 5 is benzyloxy,
  • R 6 is hydrogen or C 1 -C 3 alkyl
  • R 7 is hydrogen, C 1 -C 3 alkyl, n-butyl, isobutyl, tert-butyl, benzyl or M, where M is a pharmaceutically acceptable cation, and
  • R 1 is a primary or secondary C 1 -C 6 alkyl group that does not contain asymmetric carbon atoms
  • R 2 is hydrogen or C 1 -C 3 alkyl
  • R 3 is hydrogen or C 1 -C 3 alkyl, when R 2 is hydrogen, R 3 is hydrogen,
  • R 4 is hydrogen, C 1 -C 3 alkyl, trifluoromethyl or fluorine,
  • R 5 is hydrogen or methyl
  • R 5a is hydrogen or methyl, when R 4 is hydrogen, R 5 and R 5a are both hydrogen, and when R 5 is hydrogen, R 5a is hydrogen,
  • R 6 is hydrogen or methyl
  • R 7 is hydrogen, C 1 -C 2 alkyl or M, where M is a pharmaceutically acceptable cation, and
  • R 1 is a primary or secondary C 1 -C 6 alkyl group that does not contain asymmetric carbon atoms
  • R 2 is hydrogen, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, trifluoromethyl, fluorine, chlorine, phenoxy or benzyloxy,
  • R 3 is hydrogen, C 1 -C 3 alkyl, C 1 -C 2 alkoxy, fluorine or chlorine, but when R 2 is hydrogen, R 3 is hydrogen,
  • R 4 is hydrogen, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, trifluoromethyl, fluorine, chlorine, phenoxy or benzyloxy,
  • R 5 is hydrogen, C 1 -C 2 alkyl, C 1 -C 2 alkoxy, fluorine or chlorine,
  • R 5a is hydrogen or methyl, but when R 4 is hydrogen, R 5 and R 5a are both hydrogen, and when R 5 is hydrogen, R 5a is hydrogen,
  • R 6 is hydrogen or C 1 -C 2 alkyl
  • R 7 is hydrogen, C 1 -C 3 alkyl or M, where M is a pharmaceutically acceptable cation, and
  • R 1 is a C 1 -C 3 alkyl group
  • R 2 is hydrogen, C 1 -C 3 alkyl, methoxy, fluorine, chlorine or 4-, 5- or 6-benzyloxy,
  • R 3 is hydrogen or C 1 -C 3 alkyl, when R 2 is hydrogen, R 3 is hydrogen,
  • R 4 is hydrogen, methyl, methoxy, fluorine or chlorine
  • R 5 is hydrogen, methyl, methoxy, fluorine or chlorine
  • R 5a is hydrogen or methyl.
  • R 4 is hydrogen, both R 5 and R 5a are hydrogen,
  • R 5 is hydrogen
  • R 5a is hydrogen
  • R 6 is hydrogen
  • R 7 is hydrogen, C 1 -C 2 alkyl or M, where M is a pharmaceutically acceptable cation, and
  • the compound comprises a compound of formula III or a pharmaceutically acceptable salt or ester thereof:
  • M + is a pharmaceutically acceptable cation.
  • the compound is in racemic form.
  • the compound comprises a compound of formula IV or a pharmaceutically acceptable salt or ester thereof:
  • the compound has the 3R, 5S configuration.
  • the compound comprises a compound of formula V or a pharmaceutically acceptable salt or ester thereof,
  • the compound comprises a compound of formula VI or a pharmaceutically acceptable salt or ester thereof:
  • R 1 is a primary or secondary C 1 -C 6 alkyl group that does not contain asymmetric carbon atoms, C 3 -C 6 cycloalkyl group or phenyl -(CH 2 )m-, where m is 1, 2 or 3,
  • R 2 is hydrogen, C 1 -C 3 alkyl, n-butyl, isobutyl, tert-butyl, C 3 -C 6 cycloalkyl, C 1 -C 3 alkoxy, n-butoxy, isobutyl Oxy, trifluoromethyl, fluorine, chlorine, phenoxy or benzyloxy,
  • R 3 is hydrogen, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, trifluoromethyl, fluorine, chlorine, phenoxy or benzyloxy.
  • R 2 is hydrogen
  • R 3 is hydrogen
  • At most one of R 2 and R 3 is trifluoromethyl
  • at most one of R 2 and R 3 is phenoxy
  • at most one of R 2 and R 3 is benzyloxy
  • R 4 is hydrogen, C 1 -C 3 alkyl, n-butyl, isobutyl, tert-butyl, C 1 -C 3 alkoxy, n-butoxy, isobutoxy, trifluoromethyl, fluorine , Chloro, phenoxy or benzyloxy,
  • R 5 is hydrogen, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, trifluoromethyl, fluorine, chlorine, phenoxy or benzyloxy,
  • R 5a is hydrogen, C 1 -C 2 alkyl, C 1 -C 2 alkoxy, fluorine or chlorine, when R 4 is hydrogen, R 5 and R 5a are both hydrogen, and when R 5 is hydrogen, R 5a is Hydrogen, at most one of R 4 and R 5 is trifluoromethyl, at most one of R 4 and R 5 is phenoxy, and at most one of R 4 and R 5 is benzyloxy,
  • R 6 is hydrogen or C 1 -C 3 alkyl
  • R 7 is hydrogen, C 1 -C 3 alkyl, n-butyl, isobutyl, tert-butyl, benzyl or M, where M is a pharmaceutically acceptable cation, and
  • R 1 is a primary or secondary C 1 -C 6 alkyl group that does not contain asymmetric carbon atoms
  • R 2 is hydrogen, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, trifluoromethyl, fluorine, chlorine, phenoxy or benzyloxy,
  • R 3 is hydrogen, C 1 -C 3 alkyl, C 1 -C 2 alkoxy, fluorine or chlorine, when R 2 is hydrogen, R 3 is hydrogen,
  • R 4 is hydrogen, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, trifluoromethyl, fluorine, chlorine, phenoxy or benzyloxy,
  • R 5 is hydrogen, C 1 -C 2 alkyl, C 1 -C 2 alkoxy, fluorine or chlorine,
  • R 5a is hydrogen or methyl, when R 4 is hydrogen, R 5 and R 5a are both hydrogen, and when R 5 is hydrogen, R 5a is hydrogen,
  • R 6 is hydrogen or C 1 -C 2 alkyl
  • R 7 is hydrogen, C 1 -C 3 alkyl or M, where M is a pharmaceutically acceptable cation, and
  • the PRDX1 selective agonist further comprises a pharmaceutically acceptable carrier or excipient.
  • the present application provides a method for activating PRDX1, the method comprising administering an effective amount of the PRDX1 selective agonist described in the present application.
  • the method is an in vivo, in vitro, and/or ex vivo method.
  • this application provides a method for identifying PRDX1 selective agonists, the method comprising:
  • PRDX1 protein variant which contains an amino acid sequence at one or more of the 78th, 79th, and 108-124th amino acid residues of the amino acid sequence shown in SEQ ID NO:1 Each position contains one or more amino acid substitutions, additions and/or deletions.
  • the method further includes evaluating whether the substance to be identified specifically binds to the PRDX1 protein variant.
  • the present application provides a kit for identifying PRDX1 selective agonists, which comprises a PRDX1 protein variant, and the PRDX1 protein variant comprises an amino acid sequence in the amino acid sequence shown in SEQ ID NO:1.
  • One or more positions of amino acid residues 78, 79 and 108-124 contain one or more amino acid substitutions, additions and/or deletions.
  • the present application provides a method for preventing, alleviating and/or treating a disease or condition caused by the release of inflammatory factors, the method comprising administering an effective amount of PRDX1 described in the present application to a subject in need Selective agonist.
  • the disease or condition is a disease or condition associated with inflammatory factor storms.
  • the inflammatory factor storm includes a cytokine storm.
  • the release of the inflammatory factor is induced by lipopolysaccharide.
  • the disease or condition is selected from: inflammatory response syndrome (SIRS), severe pneumonia, severe lung injury, acute respiratory distress syndrome (ARDS), acute respiratory failure, sepsis, acute pancreatitis , Sepsis, systemic lupus erythematosus, rheumatic diseases, CAR-T cytokine storm, pulmonary fibrosis, liver fibrosis and antibody drug immune response.
  • SIRS inflammatory response syndrome
  • severe pneumonia severe pneumonia
  • severe lung injury acute respiratory distress syndrome
  • ARDS acute respiratory distress syndrome
  • acute respiratory failure Sepsis, acute pancreatitis , Sepsis, systemic lupus erythematosus, rheumatic diseases
  • CAR-T cytokine storm pulmonary fibrosis
  • liver fibrosis and antibody drug immune response.
  • the inflammatory factor includes TNF- ⁇ , IL-1 ⁇ , IL-6, IL-8, CCL2, CXCL10 and/or IFN ⁇ .
  • the release of the inflammatory factor is mediated by PRDX1.
  • the present application provides a use of the PRDX1 selective agonist described in the present application for the preparation of a medicament for the prevention, alleviation and/or treatment of diseases or disorders caused by the release of inflammatory factors.
  • the disease or condition is a disease or condition associated with inflammatory factor storms.
  • the inflammatory factor storm includes a cytokine storm.
  • the release of the inflammatory factor is induced by lipopolysaccharide.
  • the disease or condition is selected from: inflammatory response syndrome (SIRS), severe pneumonia, severe lung injury, acute respiratory distress syndrome (ARDS), acute respiratory failure, sepsis, acute pancreatitis , Sepsis, systemic lupus erythematosus, rheumatic diseases, CAR-T cytokine storm, pulmonary fibrosis, liver fibrosis and antibody drug immune response.
  • SIRS inflammatory response syndrome
  • severe pneumonia severe pneumonia
  • severe lung injury acute respiratory distress syndrome
  • ARDS acute respiratory distress syndrome
  • acute respiratory failure Sepsis, acute pancreatitis , Sepsis, systemic lupus erythematosus, rheumatic diseases
  • CAR-T cytokine storm pulmonary fibrosis
  • liver fibrosis and antibody drug immune response.
  • the inflammatory factor includes TNF- ⁇ , IL-1 ⁇ , IL-6, IL-8, CCL2, CXCL10 and/or IFN ⁇ .
  • the release of the inflammatory factor is mediated by PRDX1.
  • the present application provides a PRDX1 selective agonist as described in the present application, which is used to prevent, alleviate and/or treat diseases or disorders caused by the release of inflammatory factors.
  • the disease or condition is a disease or condition associated with inflammatory factor storms.
  • the inflammatory factor storm includes a cytokine storm.
  • the release of the inflammatory factor is induced by lipopolysaccharide.
  • the disease or condition is selected from: inflammatory response syndrome (SIRS), severe pneumonia, severe lung injury, acute respiratory distress syndrome (ARDS), acute respiratory failure, sepsis, acute pancreatitis , Sepsis, systemic lupus erythematosus, rheumatic diseases, CAR-T cytokine storm, pulmonary fibrosis, liver fibrosis and antibody drug immune response.
  • SIRS inflammatory response syndrome
  • severe pneumonia severe pneumonia
  • severe lung injury acute respiratory distress syndrome
  • ARDS acute respiratory distress syndrome
  • acute respiratory failure Sepsis, acute pancreatitis , Sepsis, systemic lupus erythematosus, rheumatic diseases
  • CAR-T cytokine storm pulmonary fibrosis
  • liver fibrosis and antibody drug immune response.
  • the inflammatory factor includes TNF- ⁇ , IL-1 ⁇ , IL-6, IL-8, CCL2, CXCL10 and/or IFN ⁇ .
  • the release of the inflammatory factor is mediated by PRDX1.
  • Figures 1A-1C show the activation of PRDX1 enzymatic activity by fluvastatin or its salt described in the present application.
  • Figures 2A-2C show the crystal structure of the complex of fluvastatin or its salt and PRDX1 described in the present application.
  • Figure 3 shows the SPR detection result of fluvastatin or its salt on PRDX1 according to the present application.
  • Figure 4 shows the results of MST detection of PRDX1 by fluvastatin or its salt according to the present application.
  • Figures 5A-5E show the binding sites and interactions between fluvastatin and PRDX1 described in this application.
  • Figures 6-1-6-2 include Figures 6A-6K, which show the effect of fluvastatin described in the present application on activating PRDX1 to reduce the expression of intracellular ROS and pro-inflammatory cytokines.
  • Figures 7A-7G show the enzymatic activity of seven statins on PRDX1.
  • Figures 8A-8E show the enzymatic activity of fluvastatin described in this application on six members from the human PRDX protein family.
  • Figures 9A-9F show the SPR binding curves of six statins and PRDX1 protein.
  • Figure 10 shows the sequence alignment results of the human PRDX protein family.
  • FIGS 11A-11G show the chemical structures of seven statins.
  • Figures 12A-12H show that fluvastatin inhibits the activation of NFkB by eliminating intracellular ROS in HeLa cells.
  • Figure 13 shows the data collection and statistical information of the composite crystal of fluvastatin and PRDX1 described in this application.
  • fluvastatin usually refers to fluvastatin, its chemical formula is C 24 H 26 FNO 4 , and its chemical name is 7-[3-(4-fluorophenyl)-1-(1-methyl) Ethyl)-1H-indol-2-yl]-3,5-dihydroxy-6-heptenoic acid, and has the following structural formula:
  • Fluvastatin can block the liver enzyme HMG-CoA reductase, thereby inhibiting the synthesis of cholesterol.
  • Fluvastatin belongs to the class of statins.
  • Statins can be 3-hydroxy-3 methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, and are usually used as lipid-lowering drugs.
  • HMG-CoA 3-hydroxy-3 methylglutaryl-coenzyme A
  • Currently common statins can be selected from the following group: lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin and pitavastatin.
  • PRDX1, Peroxiredoxins 1 generally refers to the protein encoded by the PRDX1 gene, which may also be referred to as MSP 23, NKEF-A, PAG, PAGA or PRX1.
  • PRDX1 belongs to the peroxidase family of antioxidant enzymes. Cells can be stimulated by LPS or TNF- ⁇ to release PRDX1. The released PRDX1 can produce inflammatory cytokines. PRDX1 can be overexpressed in cancer cells, such as prostate cancer.
  • the accession number of human PRDX1 in UniProt is Q06830.
  • the term "PRDX1 enzymatic activity” generally refers to the enzymatic activity possessed by PRDX1.
  • the PRDX1 enzyme activity may include the reducing activity (or antioxidant activity) of PRDX1.
  • the PRDX1 enzyme activity may include oxidation of cysteine with redox activity at the active site of PRDX1 by peroxide to sulfinic acid.
  • the PRDX1 enzyme activity may include reducing peroxides (e.g., hydrogen peroxide and alkyl hydroperoxides). The PRDX1 enzyme activity can control cytokine-induced peroxide levels.
  • the term "selective agonist” generally refers to a specific agonist.
  • the agonist may be a compound that binds to the receptor and activates it, thereby generating a response and/or possessing properties.
  • the PRDX1 selective agonist can specifically bind to PRDX1 and activate PRDX1 enzyme activity.
  • the PRDX1 selective agonist may not bind to and/or not activate other peroxidase family antioxidant enzymes (for example, PRDX2-PRDX6) other than PRDX1.
  • water bridge hydrogen bond network generally refers to a hydrogen bond network formed by more than one water bridge hydrogen bond.
  • the hydrogen bond is the force between molecules (for example, permanent dipole).
  • the hydrogen bond may occur between a hydrogen atom that has been covalently bonded to another atom and another atom (X-H...Y).
  • Water can form hydrogen bonds with potentially suitable groups such as hydroxyl, amino, carbonyl, amide, or imino. Among them, a water molecule can interact with two suitable hydrogen bonding sites of one or more solute molecules to generate water bridge hydrogen bonds.
  • the hydrophilic group of the crystalline macromolecule can also form the water bridge hydrogen bond.
  • the term "superoxide” generally refers to a compound (e.g., reducing agent) containing the superoxide anion is oxidized to (superoxide ions, O 2 -) process.
  • the PRDX1 undergoes a redox reaction with the oxidizing agent H 2 O 2 , and PRDX1 can be oxidized (for example, can be super-oxidized).
  • the term "increase in the level of ROS caused by H 2 O 2 stimulation” generally refers to a process in which the redox reaction induced/participated by H 2 O 2 increases the level of ROS (reactive oxygen species).
  • the ROS may include oxygen ions, peroxides, and oxygen-containing free radicals. The increased level of ROS can cause damage to the cell and/or gene structure.
  • the term "pharmaceutically acceptable salt or ester” generally refers to a pharmaceutically acceptable salt and/or a pharmaceutically acceptable ester.
  • the pharmaceutically acceptable salt may include its acid addition salt and its base addition salt.
  • the acid addition salt can be formed from an acid that forms the pharmaceutically acceptable salt.
  • the acid addition salt may include acetate, adipate, aspartate, benzoate, benzenesulfonate, bicarbonate/carbonate, bisulfate/sulfate, Borate, camphorsulfonate, citrate, cyclamate, ethanedisulfonate, ethanesulfonate, formate, fumarate, glucoheptonate, gluconate, glucose Uronic acid salt, hexafluorophosphate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, butane Alkenate, malonate, methanesulfonate, methyl sulfate, naphthylate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate , Palmitate, pamoate, phosphate/hydrogen phosphate/
  • the base addition salt can be formed from a base that forms the pharmaceutically acceptable salt.
  • the base addition salt may include aluminum salt, arginine salt, benzathine penicillin salt, calcium salt, choline salt, diethylamine salt, diethanolamine salt, glycinate, lysine salt, magnesium salt, Meglumine, ethanolamine, potassium, sodium, tromethamine and zinc salts.
  • the pharmaceutically acceptable salt can be found in "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, 2002). The method for preparing the pharmaceutically acceptable salt may be known to those skilled in the art.
  • the pharmaceutically acceptable ester may refer to an ester derived from the PRDX1 selective agonist described in the present application (for example, each compound of the general formula described in the present application or the fluvastatin), which includes a physiologically hydrolyzable ester , which can be hydrolyzed under physiological conditions to release the PRDX1 selective agonist described in this application in free acid or alcohol form.
  • the PRDX1 selective agonist described in this application may itself be an ester.
  • the term "metabolite” generally refers to the metabolite of the PRDX1 selective agonist described in this application.
  • it may be a substance formed in the PRDX1 selective agonist described in this application.
  • prodrug generally refers to the functional group derivative of the PRDX1 selective agonist described in this application, which can be converted in vivo into a desired compound having the activity of activating the PRDX1 enzyme.
  • Design of Prodrug Elsevier, 1985 describes conventional methods for selecting and preparing suitable prodrug derivatives.
  • racemic form generally refers to the situation where two enantiomers (ie, optical isomers, Enantiomer) coexist in the form of equal amounts (for example, equal amounts of substances) (racemate) .
  • the optical rotation of the racemate may be zero.
  • the deflection of equal plane-polarized light in different directions can be offset.
  • the material properties (e.g., melting point, solubility) of the racemic form may be different from the corresponding enantiomer.
  • the term "specific binding" generally refers to a specific interaction.
  • a certain compound and its corresponding ligand may interact specifically (e.g., recognize and/or bind).
  • the specific binding may include the specific binding of the PRDX1 selective agonist to the PRDX1 (for example, a specific amino acid residue in the PRDX1).
  • the specific binding may include that the PRDX1 selective agonist only specifically binds to the PRDX1, and does not bind to other peroxidase family antioxidant enzymes (for example, PRDX2-PRDX6) other than PRDX1 Combine.
  • the term "inflammatory factor” generally refers to a factor that promotes inflammation, for example, it may include a cytokine that promotes inflammation (Proinflammatory cytokine).
  • the inflammatory factor may include IL1, TNF ⁇ , IL6 and/or IFN ⁇ .
  • disease or disorder generally refers to a disease or disorder caused by the release of the inflammatory factor.
  • the disease or condition may include the type of disease involved in clinical classification standards, and may also include the corresponding symptoms.
  • the disease or disorder includes any abnormal life activity process caused by the release of the inflammatory factor, which may affect part or all organs of the organism, and may also be accompanied by specific symptoms and/or medical signs.
  • the term "inflammatory factor storm” generally refers to the excessive immune response caused by the inflammatory factor, which brings about autoimmune damage.
  • the inflammatory factor storm may be caused by excessive activation of immune cells, and the inflammatory factors are released in large quantities, and suicide attacks are carried out on the source of infection or infected cells, causing bystander damage to their own tissue cells.
  • the symptoms of the inflammatory factor storm may include increased vascular permeability, circulatory disturbance, and multiple organ failure (MOF).
  • the inflammatory factor storm may include a cytokine storm (Cytokine storm).
  • the cytokine storm may include an inappropriate immune response generated by the positive feedback loop between the cytokine and immune cells.
  • the symptoms of the cytokine storm may include high fever, redness, swelling, fatigue, and nausea.
  • SIRS Inflammatory Response Syndrome
  • Systemic inflammatory response syndrome Systemic inflammatory response syndrome
  • the pathophysiological activity pathway of SIRS may include fibrin deposition, platelet aggregation, coagulation dysfunction, and leukocyte liposome release.
  • the symptoms of SIRS may include renal failure, ARDS, central nervous system dysfunction, and gastrointestinal bleeding.
  • the SIRS diagnostic criteria may include body temperature, heart rhythm, respiratory rate, and WBC.
  • the term "effective amount” generally refers to the dose at which an effective effect and/or pharmacological effect occurs.
  • the effective amount may be a threshold amount.
  • the effective amount may be the minimum effective amount, that is, the minimum dose at which an effective effect and/or a pharmacological effect occurs.
  • the effective amount can also be a dose between the minimum effective amount and the maximum dose (for example, a dose that is intolerable and/or causes toxic side effects) (in some cases, an endpoint may also be included).
  • the effective amount may refer to the dose required for the PRDX1 selective agonist to activate PRDX1.
  • the effective amount may refer to the dose required for the PRDX1 selective agonist to prevent, alleviate and/or treat the disease or condition caused by the release of the inflammatory factor.
  • the effective amount can adjust to obtain the required effective amount of the application with the help of the usual receipt in the art.
  • this application provides a peroxidase reductase 1 (PRDX1) selective agonist, which comprises a compound capable of activating the activity of the PRDX1 enzyme, and the compound is selected from among the PRDX1
  • PRDX1 peroxidase reductase 1
  • One or more amino acid residues from the following group interact specifically: the 78th, 79th and 108th-124th amino acid residues of SEQ ID NO:1.
  • the compound may specifically bind to the one or more amino acid residues of the PRDX1.
  • the one or more amino acid residues may include the 110th amino acid of SEQ ID NO:1.
  • the compound can form a hydrogen bond with the side chain of the 110th amino acid of SEQ ID NO:1.
  • the compound can form a water bridge hydrogen bond network with the PRDX1 through the 78th amino acid residue and/or the 79th amino acid residue of the SEQ ID NO:1.
  • the compound can increase the super-oxidation of PRDX1 in H 2 O 2 treatment compared to treatment with H 2 O 2 alone.
  • the compound can increase the level of super-oxidation of PRDX1 in H 2 O 2 treatment by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%. %, at least 60%, at least 70%, at least 80%, at least 90%, at least 100%, at least 150%, at least 200% or more.
  • the compound can inhibit the increase in ROS level caused by H 2 O 2 stimulation.
  • the compound can suppress the increase in ROS levels by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%. , At least 70%, at least 80%, at least 90%, at least 100%, at least 150%, at least 200% or more.
  • the compound may not substantially activate the enzymatic activity of PRDX2, PRDX3, PRDX4, PRDX5, and/or PRDX6.
  • the substantially inactivation may include that the compound has reduced the activation level of PRDX2, PRDX3, PRDX4, PRDX5 and/or PRDX6 by at least 80%, at least 90%, at least as compared with PDRX1. 95% or more.
  • the compound may include fluvastatin, its prodrug, its metabolite or derivative, or its pharmaceutically acceptable salt or ester.
  • the compound may comprise a compound of formula I or a pharmaceutically acceptable salt or ester thereof:
  • R and R 0 is And the other is a primary or secondary C 1 -C 6 alkyl, C 1 -C 3 cycloalkyl or phenyl -(CH 2 ) m -that does not contain asymmetric carbon atoms, wherein R 4 is hydrogen, and C 1- C 3 alkyl, n-butyl, isobutyl, tert-butyl, C 1 -C 3 alkoxy, n-butoxy, isobutoxy, trifluoromethyl, fluorine, chlorine, phenoxy or benzyl Oxy,
  • R 5 is hydrogen, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, trifluoromethyl, fluorine, chlorine, phenoxy or benzyloxy,
  • R 5a is hydrogen, C 1 -C 2 alkyl, C 1 -C 2 alkoxy, fluorine or chlorine, and
  • n 1, 2 or 3 when R 4 is hydrogen, R 5 and R 5a are both hydrogen, when R 5 is hydrogen, R 5a is hydrogen, one of R 4 and R 5 is trifluoromethyl, R 4 At most one of and R 5 is a phenoxy group, and at most one of R 4 and R 5 is a benzyloxy group,
  • R 2 is hydrogen, C 1 -C 3 alkyl, n-butyl, isobutyl, tert-butyl, C 3 -C 6 cycloalkyl, C 1 -C 3 alkoxy, n-butoxy, isobutyl Oxy, trifluoromethyl, fluorine, chlorine, phenoxy or benzyloxy,
  • R 3 is hydrogen, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, trifluoromethyl, fluorine, chlorine, phenoxy or benzyloxy.
  • R 2 is hydrogen
  • R 3 is hydrogen
  • At most one of R 2 and R 3 is trifluoromethyl
  • at most one of R 2 and R 3 is phenoxy
  • at most one of R 2 and R 3 is benzyloxy
  • R 6 is hydrogen or C 1 -C 3 alkyl
  • R 7 is hydrogen, C 1 -C 3 alkyl, n-butyl, isobutyl, tert-butyl, benzyl or M, where M is a cation.
  • the M may be a pharmaceutically acceptable cation.
  • the compound may comprise a compound of formula II or a pharmaceutically acceptable salt or ester thereof:
  • R 1 is a primary or secondary C 1 -C 6 alkyl group that does not contain asymmetric carbon atoms, C 3 -C 6 cycloalkyl group or phenyl -(CH 2 )m-, where m is 1, 2 or 3,
  • R 2 is hydrogen, C 1 -C 3 alkyl, n-butyl, isobutyl, tert-butyl, C 3 -C 6 cycloalkyl, C 1 -C 3 alkoxy, n-butoxy, isobutyl Oxy, trifluoromethyl, fluorine, chlorine, phenoxy or benzyloxy,
  • R 3 is hydrogen, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, trifluoromethyl, fluorine, chlorine, phenoxy or benzyloxy.
  • R 2 is hydrogen
  • R 3 is hydrogen
  • At most one of R 2 and R 3 is trifluoromethyl
  • at most one of R 2 and R 3 is phenoxy
  • at most one of R 2 and R 3 is benzyloxy
  • R 4 is hydrogen, C 1 -C 3 alkyl, n-butyl, isobutyl, tert-butyl, C 1 -C 3 alkoxy, n-butoxy, isobutoxy, trifluoromethyl, fluorine , Chloro, phenoxy or benzyloxy,
  • R 5 is hydrogen, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, trifluoromethyl, fluorine, chlorine, phenoxy or benzyloxy,
  • R 5a is hydrogen, C 1 -C 2 alkyl, C 1 -C 2 alkoxy, fluorine or chlorine, when R 4 is hydrogen, R 5 and R 5a are both hydrogen, and when R 5 is hydrogen, R 5a is Hydrogen, at most one of R 4 and R 5 is trifluoromethyl, at most one of R 4 and R 5 is phenoxy, and at most one of R 4 and R 5 is benzyloxy,
  • R 6 is hydrogen or C 1 -C 3 alkyl
  • R 7 is hydrogen, C 1 -C 3 alkyl, n-butyl, isobutyl, tert-butyl, benzyl or M, where M is a pharmaceutically acceptable cation, and
  • R 1 can be a primary or secondary C 1 -C 6 alkyl group that does not contain asymmetric carbon atoms
  • R 2 can be hydrogen or C 1 -C 3 alkyl
  • R 3 can be hydrogen or C 1 -C 3 alkyl, when R 2 is hydrogen, R 3 is hydrogen,
  • R 4 can be hydrogen, C 1 -C 3 alkyl, trifluoromethyl or fluorine,
  • R 5 can be hydrogen or methyl
  • R 5a can be hydrogen or methyl, when R 4 is hydrogen, R 5 and R 5a are both hydrogen, and when R 5 is hydrogen, R 5a is hydrogen,
  • R 6 can be hydrogen or methyl
  • R 7 can be hydrogen, C 1 -C 2 alkyl or M, where M is a pharmaceutically acceptable cation, and
  • R 1 can be a primary or secondary C 1 -C 6 alkyl group that does not contain asymmetric carbon atoms
  • R 2 can be hydrogen, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, trifluoromethyl, fluorine, chlorine, phenoxy or benzyloxy,
  • R 3 can be hydrogen, C 1 -C 3 alkyl, C 1 -C 2 alkoxy, fluorine or chlorine, but when R 2 is hydrogen, R 3 is hydrogen,
  • R 4 can be hydrogen, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, trifluoromethyl, fluorine, chlorine, phenoxy or benzyloxy,
  • R 5 can be hydrogen, C 1 -C 2 alkyl, C 1 -C 2 alkoxy, fluorine or chlorine,
  • R 5a can be hydrogen or methyl, but when R 4 is hydrogen, R 5 and R 5a are both hydrogen, and when R 5 is hydrogen, R 5a is hydrogen,
  • R 6 can be hydrogen or C 1 -C 2 alkyl
  • R 7 can be hydrogen, C 1 -C 3 alkyl or M, where M is a pharmaceutically acceptable cation, and
  • R 1 can be a C 1 -C 3 alkyl group
  • R 2 can be hydrogen, C 1 -C 3 alkyl, methoxy, fluorine, chlorine or 4-, 5- or 6-benzyloxy,
  • R 3 can be hydrogen or C 1 -C 3 alkyl, when R 2 is hydrogen, R 3 is hydrogen,
  • R 4 can be hydrogen, methyl, methoxy, fluorine or chlorine
  • R 5 can be hydrogen, methyl, methoxy, fluorine or chlorine
  • R 5a can be hydrogen or methyl. When R 4 is hydrogen, both R 5 and R 5a are hydrogen. When R 5 is hydrogen, R 5a is hydrogen.
  • R 6 can be hydrogen
  • R 7 can be hydrogen, C 1 -C 2 alkyl or M, where M is a pharmaceutically acceptable cation, and
  • the compound may comprise a compound of formula III or a pharmaceutically acceptable salt or ester thereof:
  • M + is a pharmaceutically acceptable cation.
  • the compound may be in racemic form.
  • the compound may comprise a compound of formula IV or a pharmaceutically acceptable salt or ester thereof:
  • the compound may have a 3R, 5S configuration. That is, the compound includes the structure of the above formula IV, and the configuration is R (rectus) with the third carbon atom as the center; and the configuration is S (sinister) with the fifth carbon atom as the center.
  • the compound may comprise a compound of formula V or a pharmaceutically acceptable salt or ester thereof,
  • the compound may comprise a compound of formula VI or a pharmaceutically acceptable salt or ester thereof:
  • R 1 is a primary or secondary C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl or phenyl -(CH 2 ) m -that does not contain asymmetric carbon atoms, where m is 1, 2 or 3,
  • R 2 is hydrogen, C 1 -C 3 alkyl, n-butyl, isobutyl, tert-butyl, C 3 -C 6 cycloalkyl, C 1 -C 3 alkoxy, n-butoxy, isobutyl Oxy, trifluoromethyl, fluorine, chlorine, phenoxy or benzyloxy,
  • R 3 is hydrogen, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, trifluoromethyl, fluorine, chlorine, phenoxy or benzyloxy.
  • R 2 is hydrogen
  • R 3 is hydrogen
  • At most one of R 2 and R 3 is trifluoromethyl
  • at most one of R 2 and R 3 is phenoxy
  • at most one of R 2 and R 3 is benzyloxy
  • R 4 is hydrogen, C 1 -C 3 alkyl, n-butyl, isobutyl, tert-butyl, C 1 -C 3 alkoxy, n-butoxy, isobutoxy, trifluoromethyl, fluorine , Chloro, phenoxy or benzyloxy,
  • R 5 is hydrogen, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, trifluoromethyl, fluorine, chlorine, phenoxy or benzyloxy,
  • R 5a is hydrogen, C 1 -C 2 alkyl, C 1 -C 2 alkoxy, fluorine or chlorine, when R 4 is hydrogen, R 5 and R 5a are both hydrogen, and when R 5 is hydrogen, R 5a is Hydrogen, at most one of R 4 and R 5 is trifluoromethyl, at most one of R 4 and R 5 is phenoxy, and at most one of R 4 and R 5 is benzyloxy,
  • R 6 is hydrogen or C 1 -C 3 alkyl
  • R 7 is hydrogen, C 1 -C 3 alkyl, n-butyl, isobutyl, tert-butyl, benzyl or M, where M is a pharmaceutically acceptable cation, and
  • R 1 can be a primary or secondary C 1 -C 6 alkyl group that does not contain asymmetric carbon atoms
  • R 2 can be hydrogen, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, trifluoromethyl, fluorine, chlorine, phenoxy or benzyloxy,
  • R 3 can be hydrogen, C 1 -C 3 alkyl, C 1 -C 2 alkoxy, fluorine or chlorine, when R 2 is hydrogen, R 3 is hydrogen,
  • R 4 can be hydrogen, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, trifluoromethyl, fluorine, chlorine, phenoxy or benzyloxy,
  • R 5 can be hydrogen, C 1 -C 2 alkyl, C 1 -C 2 alkoxy, fluorine or chlorine,
  • R 5a can be hydrogen or methyl, when R 4 is hydrogen, R 5 and R 5a are both hydrogen, and when R 5 is hydrogen, R 5a is hydrogen,
  • R 6 can be hydrogen or C 1 -C 2 alkyl
  • R 7 can be hydrogen, C 1 -C 3 alkyl or M, where M is a pharmaceutically acceptable cation, and
  • the PRDX1 selective agonist may also include a pharmaceutically acceptable carrier or excipient.
  • the PRDX1 selective agonist may include the compound described in US Patent No. 5,354,772.
  • the PRDX1 selective agonist may be fluvastatin.
  • the present application provides a method for activating PRDX1, the method comprising administering an effective amount of the PRDX1 selective agonist described in the present application.
  • the method can be an in vivo, in vitro, and/or ex vivo method.
  • the methods described in this application may include promoting, stimulating, or increasing PRDX1 enzyme activity in vivo or in vitro or in vitro.
  • administration of the PRDX1 selective agonist described in this application can increase the PRDX1 enzyme activity by at least about 5%, at least about 10%, or at least about 25%. %, at least about 50%, at least about 100%, at least about 500% or more.
  • the method can be performed in various environments, such as a cell-free environment, a cell environment (e.g., cell culture), a multicellular environment (e.g., tissue or other multicellular structures), and/or in vivo conditions.
  • this application provides a method for identifying PRDX1 selective agonists, the method comprising:
  • PRDX1 protein variant which contains an amino acid sequence at one or more of the 78th, 79th and 108th-124th amino acid residues of the amino acid sequence shown in SEQ ID NO:1 Each position contains one or more amino acid substitutions, additions and/or deletions.
  • the method may further include evaluating whether the substance to be identified specifically binds to the PRDX1 protein variant.
  • the substance to be identified can be used as a PRDX1 selective agonist or its candidate drug.
  • the substance to be identified is in contact with the PRDX1 protein variant, it cannot specifically bind to the PRDX1 protein variant, or does not substantially bind to the PRDX1 protein variant (for example, the PRDX1 protein variant)
  • the IC 50 value of the substance to be identified combined with the PRDX1 protein variant is greater than about 50 nM or higher; or, the substance to be identified can bind to other PRDX proteins), then the substance to be identified cannot become the PRDX1 Selective agonist.
  • the present application provides a kit for identifying PRDX1 selective agonists, which comprises a PRDX1 protein variant, and the PRDX1 protein variant comprises an amino acid sequence in the amino acid sequence shown in SEQ ID NO:1.
  • One or more positions of amino acid residues 78, 79 and 108-124 contain one or more amino acid substitutions, additions and/or deletions.
  • the kit may include reagents for detecting the specific binding level of the substance to be identified with the PRDX1 protein variant.
  • the reagents may include reagents required for experiments with peroxidase (for example, NADPH-related enzyme activity experiments). In this application, these required reagents can be divided into different packages or mixed in a reaction mixing system.
  • the present application provides a method for preventing, alleviating and/or treating a disease or condition caused by the release of inflammatory factors, the method comprising administering to a subject in need an effective amount of the PRDX1 selective Agonist.
  • the disease or condition may be a disease or condition associated with inflammatory factor storm.
  • the inflammatory factor storm may include a cytokine storm.
  • the release of the inflammatory factor can be induced by lipopolysaccharide.
  • the lipopolysaccharide may be derived from the cell wall of gram-negative bacteria, and the lipopolysaccharide may bind to receptors on the surface of immune cells (such as CD14) and induce the activation of transcription factors such as NF- ⁇ B, and activate immune cells to secrete the Inflammatory factors.
  • peptidoglycan for example, derived from the cell wall of Gram-positive bacteria
  • the disease or condition can be selected from: inflammatory response syndrome (SIRS), severe pneumonia, severe lung injury, acute respiratory distress syndrome (ARDS), acute respiratory failure, sepsis, acute pancreatitis, sepsis, systemic Lupus erythematosus, rheumatic diseases, CAR-T cytokine storm, pulmonary fibrosis, liver fibrosis and immune response to antibody drugs.
  • SIRS inflammatory response syndrome
  • severe pneumonia severe pneumonia
  • severe lung injury acute respiratory distress syndrome
  • ARDS acute respiratory distress syndrome
  • acute respiratory failure sepsis
  • acute pancreatitis sepsis
  • systemic Lupus erythematosus sepsis
  • CAR-T cytokine storm CAR-T cytokine storm
  • pulmonary fibrosis liver fibrosis
  • immune response to antibody drugs e.g., pulmonary fibrosis, liver fibrosis and immune response to antibody drugs.
  • the inflammatory factor may include TNF- ⁇ , IL-1 ⁇ , IL-6, IL-8, CCL2, CXCL10 and/or IFN ⁇ .
  • the release of the inflammatory factor may be mediated by PRDX1.
  • the present application provides a use of the PRDX1 selective agonist described in the present application for the preparation of a medicament for the prevention, alleviation and/or treatment of diseases or disorders caused by the release of inflammatory factors.
  • the disease or condition may be a disease or condition associated with inflammatory factor storm.
  • the inflammatory factor storm may include a cytokine storm.
  • the release of the inflammatory factor can be induced by lipopolysaccharide.
  • the disease or condition can be selected from: inflammatory response syndrome (SIRS), severe pneumonia, severe lung injury, acute respiratory distress syndrome (ARDS), acute respiratory failure, sepsis, acute pancreatitis, sepsis, systemic Lupus erythematosus, rheumatic diseases, CAR-T cytokine storm, pulmonary fibrosis, liver fibrosis and immune response to antibody drugs.
  • SIRS inflammatory response syndrome
  • severe pneumonia severe pneumonia
  • severe lung injury acute respiratory distress syndrome
  • ARDS acute respiratory distress syndrome
  • acute respiratory failure sepsis
  • acute pancreatitis sepsis
  • systemic Lupus erythematosus sepsis
  • CAR-T cytokine storm CAR-T cytokine storm
  • pulmonary fibrosis liver fibrosis
  • immune response to antibody drugs e.g., pulmonary fibrosis, liver fibrosis and immune response to antibody drugs.
  • the inflammatory factor may include TNF- ⁇ , IL-1 ⁇ , IL-6, IL-8, CCL2, CXCL10 and/or IFN ⁇ .
  • the release of the inflammatory factor may be mediated by PRDX1.
  • the present application provides a PRDX1 selective agonist as described in the present application, which is used to prevent, alleviate and/or treat diseases or disorders caused by the release of inflammatory factors.
  • the disease or condition may be a disease or condition associated with inflammatory factor storm.
  • the inflammatory factor storm may include a cytokine storm.
  • the release of the inflammatory factor can be induced by lipopolysaccharide.
  • the disease or condition can be selected from: inflammatory response syndrome (SIRS), severe pneumonia, severe lung injury, acute respiratory distress syndrome (ARDS), acute respiratory failure, sepsis, acute pancreatitis, sepsis, systemic Lupus erythematosus, rheumatic diseases, CAR-T cytokine storm, pulmonary fibrosis, liver fibrosis and immune response to antibody drugs.
  • SIRS inflammatory response syndrome
  • severe pneumonia severe pneumonia
  • severe lung injury acute respiratory distress syndrome
  • ARDS acute respiratory distress syndrome
  • acute respiratory failure sepsis
  • acute pancreatitis sepsis
  • systemic Lupus erythematosus sepsis
  • CAR-T cytokine storm CAR-T cytokine storm
  • pulmonary fibrosis liver fibrosis
  • immune response to antibody drugs e.g., pulmonary fibrosis, liver fibrosis and immune response to antibody drugs.
  • the inflammatory factor may include TNF- ⁇ , IL-1 ⁇ , IL-6, IL-8, CCL2, CXCL10 and/or IFN ⁇ .
  • the release of the inflammatory factor may be mediated by PRDX1.
  • the cDNA encoding the full-length PRDX1 (M1-K199) or the c-terminally truncated PRDX1 (M1-A175) was inserted into the E. coli expression vector pET28a(+).
  • the expression plasmid was transformed into E. coli BL21 (DE3) strain, and then the transformed cells were cultured in 2 ⁇ YT medium containing 50 ⁇ g/ml kanamycin. When the cells grew to an O.D. value of 0.8, the culture temperature was changed from 37°C to 16°C, and 500 ⁇ M IPTG was used to induce protein expression. After 16 hours, the cells were collected by centrifugation.
  • the cell pellet was suspended in buffer A (20 mM Tris-HCl pH 7.0, 200 mM NaCl, 1 ⁇ ⁇ -mercaptoethanol), lysed by ultrasonic treatment, and then centrifuged at 18,000 rpm for 60 minutes. After centrifugation, the supernatant was added to the His Trap FF column (5 mL column volume, GE), and washed with buffer A containing 100 mM imidazole. The protein was eluted with buffer A containing 500 mM imidazole. Desalt the purified protein into buffer B (20mM Hepes pH7.0, 100mM NaCl).
  • the His tag of the c-terminally truncated PRDX1 was cleaved by the tobacco etch virus protease.
  • the protein was further purified by size exclusion chromatography (20mM Tris-HCl 8.0, 100mM NaCl) in buffer C. The protein was concentrated to 10 mg/mL for crystallization.
  • the compound library used for drug screening is called the anti-cardiovascular disease compound library (Cat. No. L5400), which was purchased from TargetMol Co. Ltd.
  • the compounds in this library are stored in 96-well plates at a stock concentration of 10 mM.
  • analytically pure powdered fluvastatin sodium product number CSN13091
  • atorvastatin hemicalcium product number CSN12530
  • pravastatin sodium product number CSN12298
  • lovastatin product number CSN11335
  • simva Statins Cat. No. CSN11927
  • Pitavastatin calcium Cat. No. CSN11738
  • Rosuvastatin calcium Cat. No. CSN12558
  • the standard Trx-Trx reductase-NADPH coupling method was used to study the activity of peroxidase family proteins.
  • the reaction was carried out on a 384-well flat bottom plate.
  • the reaction mixture contained 20 mM Hepes buffer pH 7.0, 3 ⁇ M Trx, 1.5 ⁇ M Trx reductase, 1 mM EDTA and 250 ⁇ M NADPH.
  • the peroxidase family proteins are added to the reaction mixture separately.
  • the reaction was initiated by 100 ⁇ M hydrogen peroxide. Before adding the protein to the reaction, the drug is incubated with peroxidase.
  • MST Micro thermophoresis
  • the MST assay (MA-052 NanoTemper Technologies, Kunststoff, Germany) was performed on Monolith NT automation at 25°C. The determination was carried out in MST assay buffer 20mM Hepes pH7.0, 100mM NaCl, 0.1% Pluronic F-127 by the label-free method. In the standard binding affinity experiment, the working concentration of PRDX1 protein was set to 12 ⁇ M, and the highest concentration of fluvastatin was 25 ⁇ M. Use expert mode to calculate kinetic constants in MO.Affinity Analysis v2.3 software.
  • PRDX1 protein was crystallized by the 18°C seating method.
  • the crystals were grown in a well solution buffer containing 10% v/v acetic acid pH 7.5, 0.1M MES pH 6.5, and 25% PEG4000.
  • fluvastatin was re-dissolved in the pore solution to a final concentration of 1 mM, and then the Apo crystals of PRDX1 were soaked in the pore solution containing 1 mM fluvastatin. The soaking process is maintained for at least 72h.
  • the crystals were transferred to a cryoprotectant solution: 30% glycerol-containing pore solution, and then the crystals were quickly frozen in liquid nitrogen.
  • the X-ray diffraction data was collected on the BL19U1 beamline of the Shanghai Synchrotron Radiation Facility (SSRF). The data was integrated using XDS software package 3, and the Scala module 4 of CCP4 software 5 was used for scaling.
  • the dimer of PRDX1 (PDB code: 4XCS) as a search template, the structure was determined by molecular substitution with Phaser module 6 of Phenix7.
  • the initial model after molecular replacement is fixed using ARP module 8 of CCP4 and Coot9.
  • Use Phenix's LigandFit module 10 to determine the atomic coordinates of fluvastatin based on the electron density neglect map.
  • the final model was adjusted in Coot and completed after a perfect cycle in Phenix.
  • Figure 13 is the statistical information of crystal data collection and refining of the composite crystal of fluvastatin and PRDX1 (PRDX1-fluvastatin).
  • Atomic coordinates and structure factor files have been stored in the protein database (PDB), the accession number is 7BXJ.
  • CM-DCFH carboxyl DCFH
  • Oxidation products in short, Raw 264.7 or Hela cells treated with LPS/TNF ⁇ /H 2 O 2 were starved in Hank's buffer for 30 minutes, and then incubated in CM-DCFH at 5°C for 30 minutes at 37°C. Then use a fluorometer (BioTek) to detect under dark conditions at an excitation wavelength of 485nm and an emission wavelength of 520nm.
  • Lysis of cells 1% deoxycholic acid, 10mM Na 4 P 2 O 7 , 1% Triton 100, 100 mM NaCl, 5 mM EDTA, 50 mM Tris-HCl, 0.1% SDS
  • BCA protein assay kit 23228; 23224, Thermo Fisher Scientific, Rockford, USA
  • the membrane After sealing the membrane with 5% skimmed milk in TBST, the membrane is combined with antiperoxidase SO3 (1:1000 dilution, ab16830, Abcam), PRDX1 (1:1000 dilution, 8499, Cell Signaling Technology, Danvers). Anti-incubation, Massachusetts, USA), phosphor-NF- ⁇ Bp65 (1:1000 dilution, 3033, Cell Signal Technology Company), NF- ⁇ Bp65 (1:1000 dilution, 8242, Cell Signal Technology), I- ⁇ B( 1:1000 dilution, 9242, Cell Signaling Technology) or actin (1:10000 dilution, Cell Signaling Technology) at 4°C overnight, and then place the secondary antibody at room temperature for 1 hour. Finally, an ECL detection system is used to generate the signal.
  • the constructed PRDX1 enzyme activity belongs to the standard enzyme activity method based on NADPH oxidation.
  • the specific method is: in the experiment, first incubate the small molecule and peroxidoreductase PRDX1 at 37°C for 25 minutes, and then add 20mM HEPES pH7.0, 5mM EDTA, 5 ⁇ M cofactor protein A, 2 ⁇ M cofactor protein B, 300 ⁇ M NADPH Prepare the pre-reaction buffer and transfer it to a 96-well detection plate (120 ⁇ l per well), then add the target protein incubated with the compound to the detection plate (final protein concentration is 200nM, volume per well is 40 ⁇ l), and finally in the system Add 40 ⁇ l 200 ⁇ M hydrogen peroxide to start the enzymatic reaction cycle.
  • the absorbance at 340nm was used to detect the oxidation of NADPH.
  • the reading of the test board is cycled every 90 seconds, and the reading is performed at least 20 cycles.
  • the initial linear part of the reading is used to characterize the consumption rate of NADPH in the system, which can indirectly reflect the consumption rate of hydrogen peroxide.
  • the working concentration of the small molecule compound was 1 ⁇ M as the highest concentration, and it was diluted twice in equal proportion.
  • Figure 1 shows the activation data of PRDX1 enzyme activity by fluvastatin or its salt.
  • Figure 1A shows the full-time curve of the enzymatic reaction kinetics of fluvastatin or its salt on PRDX1
  • Figure 1B shows the linear reaction part of the enzymatic reaction kinetics of fluvastatin or its salt on PRDX1
  • the ratio of the slope of the linear reaction part of the enzymatic reaction kinetic curve of the enzymatic reaction kinetic curve of PRDX1 on PRDX1 by vastatin or its salt is compared to the ratio of the linear reaction part of the enzymatic reaction kinetic curve of PRDX1 protein itself.
  • fluvastatin is a direct agonist of PRDX1
  • SPR surface plasmon resonance
  • MST microscale thermophoresis
  • Figures 7A-7G show FV (i.e. fluvastatin), AH (i.e. atorvastatin), LO (i.e. lovastatin), SV (i.e. Simvastatin), PS (i.e. Pravastatin), RC (i.e. Rosuvastatin) and PC (ie Pitavastatin).
  • fluvastatin did not activate the PRDX2-PRDX6 enzyme, indicating that it is a selective agonist of PRDX1 in the PRDX protein family ( Figure 8A-8E).
  • Figures 8A-8E sequentially show the interaction of fluvastatin with PRDX2, PRDX3, PRDX4, PRDX5 and PRDX6. Because fluvastatin cannot activate the PRDX2-PRDX6 enzyme, fluvastatin is a selective agonist of PRDX1.
  • Figures 9A-9F show the SPR binding curves of six statins and PRDX1 protein.
  • 9A-9F represent AT (i.e. atorvastatin), LO (i.e. Lovastatin), PC (i.e. Pitavastatin), RC (i.e. Rosuvastatin), SV (i.e. Simvastatin) and PS (i.e. That is pravastatin).
  • AT i.e. atorvastatin
  • LO i.e. Lovastatin
  • PC i.e. Pitavastatin
  • RC i.e. Rosuvastatin
  • SV i.e. Simvastatin
  • PS i.e. That is pravastatin
  • Example 2 MD-based crystal structure optimization and small molecule-protein complex crystal structure analysis
  • the PDB ID is 4XCS.
  • the C-terminal 23 amino acid residues of the protein primary sequence are too flexible, and the secondary structure is not shown, and there is a mutation of cysteine in the structure.
  • the strategy of combining cysteine mutation and C-terminal amino acid truncation one by one was adopted, and the molecular dynamics simulation trajectories of the above-mentioned proteins were submitted one by one, and the Amber software was used to develop the above-mentioned proteins on supercomputers such as Tianhe No. 1 and Tianhe No. 2 A molecular dynamics simulation on a longer time scale.
  • Figure 2A shows fluvastatin or its salt bound to one of the monomers of PRDX1 homodimer
  • Figure 2B shows the electron density shown in the crystal structure of fluvastatin or its salt
  • Figure 2C shows fluvastatin or its The interaction between the salt and the binding site of PRDX1.
  • Figure 10 shows the result of sequence alignment of the human PRDX protein family. According to the complex crystal structure of fluvastatin and PRDX1, the main binding area of PRDX1 and fluvastatin is marked at the underline.
  • fluvastatin and PRDX1 The main interaction between fluvastatin and PRDX1 involves the terminal carboxyl group of fluvastatin. It forms a hydrogen bond with the side chain of Arg-110 in PRDX1. In addition, it interacts with PRDX1 through the Val-78 and Asp-79 residues of PRDX1 through a water bridge hydrogen bond network ( Figure 2C). In addition, the unique binding mode of fluvastatin and PRDX1 can also support the following conclusions: due to steric hindrance and electrostatic repulsion, the binding of other statins to PRDX1 is weak or no binding ( Figure 11).
  • Example 3 MST and SPR characterize the binding of fluvastatin or its salt to PRDX1 protein
  • SPR Surface plasmon resonance
  • MST microthermophoresis
  • the SPR binding experiment was specifically implemented on the Biacore T200, and the PRDX1 protein was covalently coupled to the CM5 chip according to the standard operating procedure of the protein coupling chip. First, equilibrate the entire system with HBS buffer salt overnight, then use HBS buffer salt to dilute the compound and perform binding experiments for each concentration point of the compound and the protein coupled on the chip at 30 ⁇ L/min, contact time 60 seconds, and dissociation time 300 seconds . Finally, the Biacore T200 analysis software was used to calculate the binding and dissociation constant (KD) of the compound to the protein PRDX1.
  • KD binding and dissociation constant
  • the MST experiment was specifically implemented on Monolith NT.Automated (MA-052).
  • the MST protein non-labeling method was used to determine the binding and dissociation constants of the compound and PRDX1.
  • HEPES buffer salt (20mM HEPES 7.0, 100mM NaCl) was used to preserve and dilute the protein.
  • dilute small molecule compounds according to the standard operating procedure shown in the MST instrument operating software. Process the data according to the software standard operating procedure and calculate the binding and dissociation constant of the small molecule compound to the PRDX1 protein.
  • PRDX1 as a peroxidase, converts H 2 O 2 into water to form cysteine at its active cysteine site (Cys-SOH), then forms a subunit disulfide bond, which is subsequently Thioredoxin is removed, thereby starting its enzymatic reaction.
  • PRDX1 can detoxify physiologically produced intracellular hydrogen peroxide. The formation of disulfide is a slow process. When there is an excess of H 2 O 2 to provide a sufficient substrate for oxidation, the initial sulfite intermediate may be overoxidized to Cys-SO 3 .
  • fluvastatin can enhance the enzymatic reaction.
  • fluvastatin can effectively inhibit the increase in H 2 O 2 stimulated ROS levels (Figure 6B, Figure 12B). It is well known that increased H 2 O 2 is closely related to the activation of NF- ⁇ B. Correspondingly, fluvastatin treatment can block H 2 O 2 -induced phosphorylation of NF- ⁇ B ( Figure 6C, Figure 12C). In order to verify that fluvastatin clears H 2 O 2 by specifically activating PRDX1, PRDX1 knockout (KO) Hela cells were generated using the CRISPR-Cas9 method ( Figure 12D).
  • fluvastatin can inhibit the pro-inflammatory response by activating PRDX1, thereby eliminating the increase in ROS triggered by any pathogen.
  • Raw264.7 cells were treated with lipopolysaccharide (LPS) and related signal pathways were monitored. LPS increased intracellular ROS to a level, while fluvastatin effectively inhibited LPS-induced ROS production (Figure 6E).
  • fluvastatin can significantly inhibit the increase in ROS levels in Hela cells in response to TNF ⁇ stimulation ( Figure 12F).
  • fluvastatin can block NF- ⁇ B phosphorylation stimulated by LPS and TNF ⁇ ( Figure 6F, Figure 12G).
  • PRDX1KO Hela cells were treated with TNF ⁇ , and ROS levels and NF- ⁇ B activity were detected. Fluvastatin-stimulated ROS removal was abolished in PRDX1KO cells ( Figure 6J), while it was still effective in scrambled cells ( Figure 12H). As a result, fluvastatin effectively prevented the phosphorylation of NF- ⁇ B induced by TNF ⁇ in the disrupted cells, and this blocking effect was eliminated in PRDX1KO cells ( Figure 6K). This result indicates that fluvastatin exerts its anti-inflammatory effect through PRDX1. That is, fluvastatin inhibits the pro-inflammatory response by activating PRDX1 and eliminating the increased ROS in response to various pathogenic stimuli.

Abstract

L'invention concerne un agoniste sélectif de la peroxyrédoxine 1 (PRDX1). L'agoniste sélectif comprend un composé qui peut activer l'activité enzymatique du PRDX1 ; de plus, le composé interagit spécifiquement avec un ou plusieurs résidus d'acides aminés, dans le PRDX1, sélectionnés dans le groupe suivant : résidus d'acides aminés aux positions 78, 79 et 108-124 dans SEQ ID NO : 1. L'agoniste sélectif de PRDX1 peut comprendre de la fluvastatine.
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