WO2022163852A1 - Composition d'inhibition de l'expression de l'enzyme de conversion de l'angiotensine 2 (ace2) et/ou tmprss2 - Google Patents

Composition d'inhibition de l'expression de l'enzyme de conversion de l'angiotensine 2 (ace2) et/ou tmprss2 Download PDF

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WO2022163852A1
WO2022163852A1 PCT/JP2022/003677 JP2022003677W WO2022163852A1 WO 2022163852 A1 WO2022163852 A1 WO 2022163852A1 JP 2022003677 W JP2022003677 W JP 2022003677W WO 2022163852 A1 WO2022163852 A1 WO 2022163852A1
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insulin
foxo1
inhibitor
gly
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直樹 漆畑
勝幸 隠岐
誠一 吉原
啓介 大西
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株式会社 バイオミメティクスシンパシーズ
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Priority claimed from JP2021017835A external-priority patent/JP6906127B1/ja
Priority claimed from JP2021068032A external-priority patent/JP6953047B1/ja
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Priority to CN202280011900.9A priority Critical patent/CN117999099A/zh
Publication of WO2022163852A1 publication Critical patent/WO2022163852A1/fr

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    • 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
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    • 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
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    • A61K38/28—Insulins
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • 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
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/475—Growth factors; Growth regulators
    • C07K14/485—Epidermal growth factor [EGF], i.e. urogastrone
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Definitions

  • ACE2 angiotensin converting enzyme 2
  • TMPRSS2 Transmembraneprotease, serine 2
  • COVID-19 The infectious disease (COVID-19) caused by the new coronavirus (SARS-CoV2), which is said to have started infecting humans from the end of 2019, is raging all over the world, and research and development of vaccines against the virus and its therapeutic drugs are being carried out in various countries. is actively carried out.
  • SARS-CoV2 new coronavirus
  • COVID-19 develops, it triggers an excessive inflammatory reaction called cytokine storm, which was initially thought to cause death by causing abnormal pneumonia symptoms. Since then, it has become clear that symptoms are observed not only in the lungs but also in the blood vessels, the cranial nervous system, the liver, the kidneys, and other parts of the body.
  • Non-Patent Document 1 summarizes the knowledge about SARS-CoV2 so far.
  • an object of the present disclosure is to provide a composition for suppressing the gene expression level (mRNA level) of ACE2 and/or TMPRSS2, which is also related to the treatment/prevention of COVID-19.
  • invention 1 A composition for inhibiting the expression of angiotensin converting enzyme 2 (ACE2) and/or TMPRSS2, comprising: A composition, wherein the composition comprises a FoxO1 inhibitor.
  • invention 2 The composition according to Invention 1, wherein the FoxO1 inhibitor is a compound represented by the following formula or a salt thereof.
  • R1 is NH or CH2 ;
  • R5 is S or O;
  • R6 is a carboxyl group,
  • R7 is NH2 or CH3 , n is 1-11.
  • Invention 3 The composition of Invention 1, wherein the inhibitor is a compound represented by the following formula or a salt thereof.
  • R 1 is NH;
  • R 2 is NR 8 (R 8 is an alkyl group of C1 to C3);
  • R3 is F , Cl, Br, or I; each R4 is independently H or CH3 ;
  • R5 is O;
  • R6 is a carboxyl group,
  • R7 is NH2 ;
  • n is 1-11.
  • (Invention 4) The composition of invention 1, wherein said inhibitor is AS1842856 or AS1708727.
  • the composition of invention 1, wherein said FoxO1 inhibitor is an insulin-based compound.
  • Invention 6) The composition of Invention 5, wherein said insulin-based compound is wild-type insulin.
  • invention 7) The composition of invention 5, wherein said insulin-based compound is a modified insulin.
  • invention 8 The composition of invention 7, wherein the modified insulin is one or more selected from ultra-rapid-acting insulin, fast-acting insulin, intermediate-acting insulin, long-acting soluble insulin, mixed-acting insulin, and combined soluble insulin. .
  • invention 9 The composition of invention 7, wherein said modified insulin has an amino acid sequence that is 90% or more identical to human wild-type insulin.
  • invention 10 The composition of invention 7, wherein said modified insulin has an amino acid sequence that is 95% or more identical to human wild-type insulin.
  • invention 11 11.
  • the composition of invention 9 or 10 wherein said modified insulin A chain has an amino acid sequence that is 100% identical to that of human wild-type insulin.
  • invention 12 The composition of invention 1, wherein said FoxO1 inhibitor is a growth factor and/or a nucleic acid encoding same.
  • invention 13 The composition of invention 12, wherein said growth factor has 90% or more amino acid sequence identity with any selected from: IGF1, IGF2, EGF, FGF2, FGF14, VEGF, HGF.
  • invention 14 The composition of invention 13, wherein said growth factor has 95% or more amino acid sequence identity with any selected from: IGF1, IGF2, EGF, FGF2, FGF14, VEGF, HGF.
  • invention 15 The composition of invention 14, wherein said growth factor has 100% or more amino acid sequence identity with any selected from: IGF1, IGF2, EGF, FGF2, FGF14, VEGF, HGF.
  • invention 16 The composition of Invention 1, wherein the FoxO1 inhibitor is a FoxO1-acting inhibitor.
  • invention 17 The composition of invention 1, wherein said FoxO1 inhibitor is a PI3K/PDK1/Akt acting inhibitor.
  • invention 18 The composition of Invention 1, wherein the FoxO1 inhibitor is a FoxO1 gene expression inhibitor.
  • invention 19 19. The composition according to any one of Inventions 1 to 18, which is a composition for preventing or treating coronavirus infection (excluding diabetic patients).
  • Invention 20 A composition for preventing or treating a coronavirus infection, the composition comprising a FoxO1 inhibitor (excluding diabetic patients).
  • a composition of the present disclosure comprises a FoxO1 inhibitor. This can reduce the expression level of the ACE2 and/or TMPRSS2 gene.
  • Fig. 3 is a graph showing the relative expression levels of ACE2 and TMPRSS2 genes in HepG2 cells with the addition of a forkhead transcription factor FoxO1 inhibitor AS1842856 (concentrations shown below the graph). Furthermore, it is a schematic diagram of the expression induction mechanism of ACE2 and TMPRSS2 genes by FoxO1. Schematic representation of the cellular uptake assay of the recombinant protein (RBD-mFc) of the ACE2 binding domain (RBD) in the SARS-CoV2 surface protein spike protein.
  • RBD-mFc recombinant protein
  • RBD ACE2 binding domain
  • the RBD is fused with a mouse IgG-derived Fc sequence (mFc), and is incorporated into cells by immunostaining using a fluorescence-labeled antibody that recognizes mouse IgG (for example, Alexa Fluor (R) 488 antibody). It is possible to quantify the amount of RBD added.
  • mFc mouse IgG-derived Fc sequence
  • R Alexa Fluor 488 antibody
  • Recombinant protein (RBD-mFc) of the incorporated RBD protein was quantified using flow cytometry, and graphs showing relative mean fluorescence intensity.
  • FIG. 3 is a schematic diagram showing the relationship between the suppression of ACE2 and/or TMPRSS2 expression by the forkhead transcription factor FoxO1 inhibitor AS1842856 and the suppression of binding and uptake with spike protein.
  • Fig. 10 is a graph showing relative expression levels of ACE2 and TMPRSS2 genes in HepG2 cells to which wild-type insulin was added.
  • FIG. 10 is a graph showing the relative expression levels of ACE2 and TMPRSS2 genes in HepG2 cells with the addition of modified insulin.
  • FIG. Figure 10 is a graph showing the relative mean fluorescence intensity of S1 and RBD protein uptake quantified using flow cytometry.
  • FIG. 2 is a schematic diagram showing the relationship between suppression of ACE2 and/or TMPRSS2 expression by insulin and suppression of binding/uptake to spike protein.
  • 2 is a graph showing relative expression levels of ACE2 and TMPRSS2 genes in HepG2 cells to which various growth factors were added.
  • 2 is a graph showing relative expression levels of ACE2 and TMPRSS2 genes in HepG2 cells with the addition of HGF.
  • FIG. 10 is a graph showing the relative expression levels of ACE2 and TMPRSS2 genes in HepG2 cells with the addition of siRNA.
  • the term "to inhibit the expression of angiotensin converting enzyme 2 (ACE2) and/or TMPRSS2" encompasses the purpose of ameliorating a particular disease associated with ACE2 and/or TMPRSS2.
  • the term is not limited to therapeutic purposes.
  • the term encompasses the purpose of preventing the development of a particular disease even if one does not have that disease.
  • FluoroxO1 inhibitor described in this specification has a broad meaning and a narrow meaning, but is interpreted in the former meaning unless otherwise specified.
  • the term means an inhibitor that acts by directly binding to FoxO1 (herein, in the narrow sense, it is also referred to as a "FoxO1-acting inhibitor").
  • the term means an inhibitor that directly or indirectly acts on FoxO1 to inhibit the activity of FoxO1 as a transcription factor.
  • the term includes inhibitors that act on signaling pathways upstream of FoxO1.
  • a drug that directly acts on Akt and PDK1 upstream of FoxO1 to activate them.
  • Another example is a ligand for a receptor that affects the activity of FoxO1 (more specifically triggers a signaling pathway that suppresses the activity of FoxO1).
  • Receptors include insulin receptors, growth factor receptors, and the like.
  • the term encompasses insulin receptor ligands, growth factor receptor ligands.
  • the term further includes substances that inhibit the expression of "FoxO1" itself.
  • Typical examples include nucleic acids, such as antisense nucleic acids, shRNA, siRNA, miRNA and the like.
  • the definition of the term “inhibits the activity of FoxO1 as a transcription factor” can be determined by an analysis method known in the art. For example, performing a luciferase assay using a consensus sequence (GTAAA(T/C)AA) known to bind to FoxO1, and discriminating based on whether there is a significant difference in fluorescence intensity, etc. can be done. Alternatively, a commercially available ELISA-type activity detection assay (Active Motif, TransAMRFKHR (FOXO1), product number: 46396) may be used.
  • the addition of the test substance reduced the average value of the index of FOXO1 activity to 60%, compared with the value indicating the activity of FOXO1 in the control conditions in which water or a solution used as a solvent (DMSO, etc.) was added. % or less is defined as "inhibiting the activity of FoxO1 as a transcription factor.”
  • compositions for suppressing the expression level of angiotensin converting enzyme 2 (ACE2) and/or TMPRSS2 used the present disclosure provides A composition, said composition relating to a composition comprising a FoxO1 inhibitor.
  • any one or more of the following FoxO1 inhibitors may be included as active ingredients in the composition.
  • the disclosure relates to the use of any one or more of these active ingredients for the manufacture of pharmaceutical compositions.
  • ⁇ Insulin compounds ⁇ Growth factors or nucleic acids encoding them ⁇ FoxO1-acting inhibitors and/or PI3K/PDK1/Akt-acting inhibitors ⁇ FoxO1 gene expression inhibitors do.
  • compositions for Inhibiting Angiotensin Converting Enzyme 2 (ACE2) and/or TMPRSS2 Expression Using Insulin-Based Compounds comprise an insulin-based compound (eg, human insulin). This inhibits transcription of the gene for ACE2 and/or TMPRSS2 and reduces the amount of mRNA.
  • an insulin-based compound eg, human insulin
  • the "insulin-based compound” described herein means an agent that activates the insulin signaling pathway inside cells. Therefore, the “insulin-based compound” described herein includes not only the so-called “wild-type insulin” expressed in the human body, but also the “modified insulin” produced using genetic modification technology. Further, it can contain an agent that acts on pancreatic ⁇ -cells in vivo to promote the expression of insulin.
  • a preferred "insulin-based compound” is wild-type insulin or modified insulin. Examples of modified insulins include ultra-rapid-acting insulins, fast-acting insulins, intermediate-acting insulins, long-acting soluble insulins, mixed-acting insulins, combined soluble insulins.
  • the modified insulin may have an amino acid sequence identical to that of human wild-type insulin to some extent. For example, 90% or more, preferably 95% or more (eg, identity determined using blastp or the like). Wild-type insulin is a heterodimer of A chain and B chain. Therefore, the identity described here means the identity when the A chain and the B chain are linked and compared as one amino acid sequence. More preferably, the A-chain of the modified insulin has 100% amino acid sequence identity with the A-chain of human wild-type insulin.
  • Insulin acts as a factor that inhibits the transcription of the angiotensin converting enzyme 2 (ACE2) and/or TMPRSS2 genes. Therefore, the expression of these genes can be suppressed by adding insulin. This makes it possible to reduce the uptake of viruses into cells using the spike protein.
  • ACE2 angiotensin converting enzyme 2
  • TMPRSS2 TMPRSS2
  • compositions for Suppressing the Expression Level of Angiotensin Converting Enzyme 2 (ACE2) and/or TMPRSS2 Using Growth Factors comprises a growth factor. This inhibits transcription of the gene for ACE2 and/or TMPRSS2 and reduces the amount of mRNA.
  • growth factor means an entity that satisfies all of the following conditions. - At least partially containing a peptide or protein - Suppressing the activity of the intracellular FoxO1 transcription factor
  • the peptide or protein may be a naturally occurring substance or an artificially produced substance.
  • chemically modified naturally occurring proteins or peptides are also included.
  • Peptides or proteins may be in dimeric or higher forms as well as in monomeric form.
  • Peptides or proteins may be non-linear, eg cyclic.
  • an artificial linker may be appropriately provided. For example, according to a paper by Kenichiro Ito et al. (Nat Commun.
  • HGF HGF It has been reported that it functions as an agonist of the receptor.
  • growth factor receptor agonists that have not existed in the past may be developed. are also intended to be included in the term "growth factor" as used herein.
  • the species of the growth factor is not particularly limited, it is preferably human type.
  • growth factors include, but are not limited to, any one or more of the following: IGF1, IGF2, EGF, FGF2, FGF14, VEGF, HGF.
  • another growth factor may have an amino acid sequence that is somewhat identical to any of the growth factors listed above. For example, 90% or more, preferably 95% or more, and most preferably 100% (eg, identity determined using blastp or the like).
  • nucleic acids encoding the above growth factors may be incorporated into the composition.
  • Nucleic acids can be DNA and can be RNA (eg, mRNA).
  • the compositions of the present disclosure can contain the DNA described above in any form.
  • the coding region of DNA described above may be incorporated into a plasmid, vector, or the like.
  • compositions for suppressing the expression level of angiotensin converting enzyme 2 (ACE2) and/or TMPRSS2 using a FoxO1-acting inhibitor and/or a PI3K/PDK1/Akt-acting inhibitor include FoxO1-acting inhibitors and/or PI3K/PDK1/Akt-acting inhibitors. This inhibits transcription of the gene for ACE2 and/or TMPRSS2 and reduces the amount of mRNA.
  • PI3K/PDK1/Akt-acting inhibitor means an agent that satisfies all of the following three conditions. ⁇ Permeate the cell membrane to increase intracellular PIP 3 and/or act directly on at least one of PI3K, PDK1 and Akt Changing at least one activity ⁇ As a result of changing the activity, suppressing the activity of the intracellular FoxO1 transcription factor
  • PI3K/PDK1/Akt-acting inhibitor means a substance that exhibits an activating effect on PI3K/PDK1/Akt, although it is called an “inhibitor.” It is called an “inhibitor” in the sense that it consequently suppresses the activity of FoxO1.
  • Whether or not the transcription factor activity of FoxO1 is suppressed can be determined by a desired assay, as described in "1. Definition" above.
  • PIP3 is a second messenger generated by signals triggered by binding of receptors and ligands.
  • PIP 3 is generated by PI3K.
  • the generated PIP3 activates PDK1.
  • activated PDK1 activates Akt.
  • Activated Akt inhibits the activity of FoxO1. Therefore , by increasing intracellular PIP3 and/or directly acting on and activating at least one of PI3K, PDK1, and Akt, the activity of FoxO1 as a transcription factor is inhibited. can be done. This inhibits transcription of the gene for ACE2 and/or TMPRSS2 and reduces the amount of mRNA.
  • the action inhibits the transcription of the ACE2 and/or TMPRSS2 gene and reduces the amount of mRNA.
  • the FoxO1-acting inhibitor and/or the PI3K/PDK1/Akt-acting inhibitor preferably acts on each in the following manner. ⁇ Action to inhibit the activity of FoxO1 ⁇ Action to increase PIP3 , ⁇ Action to promote the activity of at least one of PI3K, PDK1, and Akt
  • the drug having an activity-inhibiting effect on FoxO1 includes, for example, compounds represented by the following formulas or salts thereof.
  • R1 is NH or CH2 ;
  • R 2 is NR 8 or CH-R 8 (R 8 : C1-C3 alkyl group),
  • R3 is F , Cl, Br, or I;
  • each R4 is independently H or CH3 ;
  • R5 is S or O;
  • R6 is a carboxyl group,
  • R7 is NH2 or CH3 , n is 1-11.
  • examples of agents that directly bind to and inhibit FoxO1 include compounds represented by the following formulas or salts thereof.
  • R 1 is NH
  • R 2 is NR 8 (R 8 is an alkyl group of C1 to C3)
  • R3 is F , Cl, Br, or I
  • each R4 is independently H or CH3
  • R5 is O
  • R6 is a carboxyl group
  • R7 is NH2
  • n is 1-11.
  • a specific example of the compound represented by the above formula or a salt thereof is AS1842856 (CAS No. 836620-48-5).
  • AS1708727 is an example of a drug that has the effect of inhibiting the activity of FoxO1.
  • agents having an activity-inhibiting effect on FoxO1 include KIS-154, chalcones, triterpenes, flavones, monoterpenoids, lignans, coumarins, and FOXO1 activity inhibitors consisting of phytochemicals. (Re-Table 2018/079715) and the like.
  • examples of drugs having an activity-promoting effect on PI3K/PDK1/Akt include the following compounds.
  • VO-Ohpic trihydrate SF1670 bpV (HOpic) These compounds are known to have the effect of indirectly promoting the activity of PI3K/PDK1/Akt by inhibiting PTEN, which acts oppositely to PI3K.
  • compositions for Suppressing the Expression Level of Angiotensin Converting Enzyme 2 (ACE2) and/or TMPRSS2 Using FoxO1 Gene Expression Inhibitor comprises a FoxO1 gene expression inhibitor. This reduces the expression level of FoxO1 itself. Then, the transcription of the ACE2 and/or TMPRSS2 gene is decreased, and the amount of mRNA is decreased.
  • FoxO1 gene expression inhibitors include inhibition of FoxO1 gene expression using siRNA (small interference RNA), miRNA (microRNA), or the like.
  • compositions of the present disclosure can be used to treat and/or prevent diseases involving angiotensin converting enzyme 2 (ACE2) and/or TMPRSS2. Specifically, they can be used for treatment and/or prevention of infectious diseases in which they are involved.
  • infectious diseases include coronavirus infections, eg infections by viruses such as SARS-CoV or SARS-CoV2. Preferably, it is an infection caused by SARS-CoV2 (COVID19). These viruses bind their spike proteins to the ACE2 receptors of human cells and use this as a springboard to enter cells.
  • RNA viruses including SARS-CV2 are prone to mutation.
  • proteins on the surface of viruses for example, spike proteins
  • vaccines there is a problem that the effects of vaccines can be avoided due to mutations in these proteins.
  • this approach has the advantage that it is less directly affected by mutations.
  • composition of the present disclosure can contribute not only to the treatment of infection but also to the prevention of infection.
  • approaches to treatment of infection based on anti-inflammatory effects but these approaches are countermeasures after infection has occurred and cannot contribute to prevention.
  • the compositions of the present disclosure can also serve as therapeutic agents in the sense that, once infection has occurred and the virus has propagated, it prevents further infection of other cells.
  • it not only that, but even before infection, by administering it in advance, it suppresses the expression of genes that are a stepping stone for virus infection, thereby preventing cell infection. It can also be used as a medicine.
  • compositions of the present disclosure may be formulated with suitable additional ingredients depending on the dosage form.
  • compositions of the present disclosure may include ingredients commonly included in pharmaceuticals. Examples of such ingredients include preservatives, preservatives, fragrances, pH adjusters, antioxidants, antifungal agents, excipients, binders, disintegrants, lubricants, and the like.
  • the FoxO1 inhibitors described herein are not intended for administration to diabetic patients.
  • Example 4-1 Example 1 (HepG2 cell culture) HepG2 cells were purchased from ATCC® (American Type Culture Collection, HB-8065). The cells were subcultured and maintained using a serum medium of DMEM (SIGMA, D8900) + 10% FBS (SIGMA, F7524).
  • SIGMA serum medium of DMEM
  • FBS F7524
  • Example 2 (Effect of FoxO1 inhibitor AS1842856) 4-2-1. Preparation of RNA HepG2 cells were seeded into each well of a 12-well plate (Corning (registered trademark), 3336) at 50,000 cells/cm 2 and cultured overnight. The next day (16-24 hours after seeding), the FoxO1 inhibitor AS1842856 was added at multiple concentrations (1 nM, 10 nM, 50 nM, 100 nM, 1 ⁇ M) or DMSO, which was used as its solvent, as a control. time) cultured. After culturing, total RNA was extracted from HepG2 cells using ReliaPrep RNA Miniprep system (Promega (registered trademark), Z6012).
  • cDNA synthesis (PrimeScript RT Master Mix; Takara (registered trademark), RR036A) was performed using 500 ng of RNA, and quantitative PCR (Thunderbird (registered trademark) Sybr qPCR Mix; TOYOBO (registered trademark), QPS -201X5) was performed.
  • a mixture for cDNA synthesis was prepared according to the following composition. 2 ⁇ l of 5x PrimeScript RT Master Mix (final concentration 1x) Total RNA 500 ng Adjusted to 10 ⁇ l total of RNase free H 2 O
  • the above mixture was processed using a Veriti 96 well Thermal Cycler manufactured by Applied Biosystems (registered trademark) under the following conditions. 37°C 15 minutes ⁇ 85°C 5 seconds ⁇ 4°C ⁇
  • the synthesized cDNA (10 ⁇ l) was diluted 10-fold with 90 ⁇ l of TE (10 mM Tris-HCl pH 8.0 + 1 mM EDTA pH 8.0). The dilutions were subjected to quantitative PCR.
  • cDNA was amplified from the above mixture using Bio-Rad (registered trademark) CFX-Connect.
  • the PCR cycle conditions were as follows. 1.95°C 1 minute (initial denaturation) 2.95°C 15 seconds (denaturation) 3.60°C 30 seconds (elongation) (Repeat steps 2-3 40 times, detect fluorescence signal each time step 3 is completed) 4. Raise the temperature from 65°C to 95°C in increments of 0.5°C, hold the temperature for 5 seconds, and then detect the fluorescence signal.
  • GAPDH Glyceraldehyde 3- phosphate dehydrogenase
  • the primer sequences for detecting each gene were as follows.
  • the expression level of each gene indicates the standardized value obtained by dividing the expression level of each gene obtained by quantitative PCR by the expression level of GAPDH. Furthermore, the expression level under the control condition (DMSO treatment) without FoxO1 inhibitor treatment is normalized to "1". It was confirmed by a melting curve that the PCR products amplified using the above primers were all single (that is, multiple types of sequences were not amplified with the same primers).
  • the incorporated mFc was stained, and the fluorescence intensity of Alexa Fluor (registered trademark) 488 per cell was measured and quantified using flow cytometry (Beckman Coulter (registered trademark), FC500). Kaluza Analysis 2.1 (Beckman Coulter (registered trademark)) was used for the analysis. Photographs of typical cells were taken using a fluorescence microscope (Keyence, BX-700).
  • FIG. 4 shows the difference in fluorescence intensity.
  • the fluorescence intensity exhibited by the cells when mFc, which is a negative control, was added was taken up only by mFc without mediated by ACE2, was nonspecifically bound by the secondary antibody, and autofluorescence of cells, which is considered to be a background signal. Subtracting the fluorescence intensity at the mFc therefore allows an accurate comparison of signal differences from more accurately incorporated RBDs.
  • FIG. 5 summarizes the mechanism of action of the FoxO1 inhibitor AS1842856 of the present disclosure, which is shown by the above experimental results, to inhibit the uptake of the novel coronavirus into cells.
  • AS1842856 acts on intracellular FoxO1 to suppress gene expression of ACE2 and/or TMPRSS2. This reduces the amount of ACE2 and/or TMPRSS2 on the cell surface. Then, the binding between the spike protein present on the virus surface and ACE2 is inhibited. In addition, the effect of TMPRSS2 to promote virus entry into cells is also suppressed. As a result, it provides preventive or therapeutic effects for infectious diseases, particularly coronaviruses, and other diseases mediated by ACE2 and/or TMPRSS2.
  • Example 3 Effect of insulin
  • HepG2 cells were seeded in each well of a 12-well plate (Corning (registered trademark), 3336) at 50,000 cells/cm 2 and cultured overnight. The next day (16-24 hours after seeding), wild-type and modified insulin were added at 10 ⁇ g/ml, or PBS( ⁇ ) was added as a control, and cultured for 3 days (about 72 hours). After culturing, total RNA extraction, cDNA synthesis, and quantitative PCR were performed as described in Example 2 above.
  • Insulin is categorized into modified insulins such as fast-acting insulin, rapid-acting insulin, intermediate-acting insulin, etc., depending on when mutations are introduced into amino acids by genetic engineering and how long the effect appears after administration and how long it lasts. It is manufactured and used properly according to the condition of the diabetic patient. Therefore, using these modified insulins, it was examined whether or not reduction in expression of ACE2 and TMPRSS2 mRNAs by wild-type insulin was observed.
  • modified insulins such as fast-acting insulin, rapid-acting insulin, intermediate-acting insulin, etc.
  • Wild-type insulin consists of a total of 51 amino acid sequences in which the A chain and B chain are linked.
  • the amino acid sequence of insulin mentioned above is shown below.
  • Isophane insulin also known as NPH insulin
  • NPH insulin is a product obtained by binding and crystallizing wild-type (regular) insulin and protamine.
  • Protamine crystalline insulin aspart is a combination and crystallization of protamine and insulin aspart.
  • Example 4 (Effect of insulin on spike protein uptake into cells) Next, we investigated whether suppression of ACE2 expression by insulin could inhibit the binding of SARS-CoV2 to host cells and their uptake into cells.
  • the Fc region of mouse IgG is fused to the S1 domain of the spike protein of SARS- CoV2 , and to the region RBD (Receptor Binding Domain, R319 to F541 ) necessary and sufficient for binding to ACE2 in S1.
  • Recombinant protein S1-mFc (Sino Biological, 40592-V05H1)
  • RBD-mFc (Sino Biological, 40592-V05H2) were prepared.
  • this result indicates that insulin inhibited the uptake of S1 and RBD into HepG2 cells, and that insulin-induced suppression of mRNA expression levels such as ACE2 inhibited the uptake of S1 and RBD into HepG2 cells. It suggests that it is suppressed to a level that can be suppressed.
  • FIG. 9 summarizes the mechanism of action by which the insulin-based compound of the present disclosure inhibits the cellular uptake of the novel coronavirus in one embodiment, as shown by the above experimental results.
  • Insulin-based compounds act on cells to suppress the expression of the ACE2 and/or TMPRSS2 genes. This reduces the amount of ACE2 and/or TMPRSS2 on the cell surface. Then, the binding between the spike protein present on the virus surface and ACE2 is inhibited. In addition, the effect of TMPRSS2 to promote virus entry into cells is also suppressed. As a result, it provides preventive or therapeutic effects for infectious diseases, particularly coronaviruses, and other diseases mediated by ACE2 and/or TMPRSS2.
  • Example 5 (Effects of growth factors) Experiments similar to Examples 1-4 were conducted. However, instead of various insulin compounds, the following growth factors were used at a concentration of 10 ng/ml. These are known to suppress FoxO1 as a downstream signal pathway. IGF1 (PeproTech, product number AF-100-11), IGF2 (PeproTech, product number AF-100-12), EGF (PeproTech, product number AF-100-15), FGF2 (PeproTech, product number AF-100-18B), FGF14 (BioVision®, product number 7347), VEGF165 (PeproTech, product number AF-100-20),
  • amino acid sequences of the above growth factors are as follows.
  • VEGF 165 https://www.peprotech.com/en/recombinant-human-vegfsub165sub-2 Ala Pro Met Ala Glu Gly Gly Gln Asn His His Glu Val Val Lys Phe Met Asp Val Tyr Gln Arg Ser Tyr Cys His Pro Ile Glu Thr Leu Val Asp Ile Phe Gln Glu Tyr Pro Asp Glu Ile Glu Tyr Ile Phe Lys Pro Ser Cys Val Pro Leu Met Arg Cys Gly Gly Cys Cys Asn Asp Glu Gly Leu Glu Cys Val Pro Thr Glu Glu Ser Asn Ile Thr Met Gln Ile Met Arg Ile Lys Pro His Gln Gly Gln His Ile Gly Glu Met Ser Phe Leu Gln His Asn Lys Cys Glu Cys Arg Pro Lys Lys Asp Arg Ala Arg Gln Glu Asn Pro Cys Gly Pro Cys Ser Glu Arg Arg Lys His Leu
  • Example 6 Effect of HGF
  • HGF R&D systems, product number 294-HGN-005/CF
  • HGF is widely known to repress FoxO1 as a downstream intracellular signaling pathway after binding to its receptor.
  • HGF is highly effective in preventing or treating infections, especially coronaviruses, and other diseases mediated by ACE2 and/or TMPRSS2.
  • the amino acid sequence of HGF is as follows. https://www.uniprot.org/uniprot/P14210 Met Trp Val Thr Lys Leu Leu Pro Ala Leu Leu Leu Gln His Val Leu Leu His Leu Leu Leu Leu Pro Ile Ala Ile Pro Tyr Ala Glu Gly Gln Arg Lys Arg Arg Asn Thr Ile His Glu Phe Lys Lys Ser Ala Lys Thr Thr Leu Ile Lys Ile Asp Pro Ala Leu Lys Ile Lys Thr Lys Lys Val Asn Thr Ala Asp Gln Cys Ala Asn Arg Cys Thr Arg Asn Lys Gly Leu Pro Phe Thr Cys Lys Ala Phe Val Phe Asp Lys Ala Arg Lys Gln Cys Leu Trp Phe Pro Phe Asn Ser Met Ser Ser Gly Val Lys Lys Glu Phe Gly His Glu Phe Asp Leu Tyr Glu Asn Ly
  • Example 7 (Effect of siRNA) Experiments similar to Examples 1-4 were conducted. However, siRNA was used to suppress the gene expression of FoxO1. As a control, siRNAs that do not suppress anything (Cell Signaling (registered trademark), product number 6568S) and those targeting the human FoxO1 gene (#1; Cell Signaling (registered trademark), product number 6242S, and # 2; Cell Signaling (registered trademark), product number 6256S, sequence information including controls not disclosed) was used. A transfection reagent (Horizon Discovery, DharmaFECT1, product number T2001-01) was used to introduce siRNA into cells. Three days (approximately 72 hours) after introduction of various siRNAs, cells were harvested and quantified by qPCR as described above.
  • FoxO1 inhibitors in general, compounds that function as FoxO1 inhibitors, even though the method of inhibition is greatly different, such as via a signal transduction pathway or in the case of direct inhibition (inhibitors, siRNA, etc.) It has been shown that it is effective as an ACE2 or TMPRSS2 expression inhibitor or a coronavirus infection inhibitor depending on the content of .

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Abstract

Le but de la présente invention consiste à fournir une composition d'inhibition de l'expression de l'enzyme de conversion de l'angiotensine 2 (ACE2) et/ou TMPRSS2. L'invention concerne une composition d'inhibition de l'expression de l'enzyme de conversion de l'angiotensine 2 (ACE2) et/ou TMPRSS2, la composition contenant un inhibiteur FoxO1.
PCT/JP2022/003677 2021-01-29 2022-01-31 Composition d'inhibition de l'expression de l'enzyme de conversion de l'angiotensine 2 (ace2) et/ou tmprss2 WO2022163852A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015095650A1 (fr) * 2013-12-19 2015-06-25 Puretein Bioscience Llc. Méthodes de traitement d'un animal
JP2016065055A (ja) * 2014-09-19 2016-04-28 国立大学法人金沢大学 骨髄性白血病の治療剤
WO2020169707A1 (fr) * 2019-02-21 2020-08-27 INSERM (Institut National de la Santé et de la Recherche Médicale) Inhibiteur de foxo1 utilisé pour traiter des infections virales latentes
JP6906127B1 (ja) * 2021-01-29 2021-07-21 株式会社 バイオミメティクスシンパシーズ アンジオテンシン転換酵素２（ａｃｅ２）及び／若しくはｔｍｐｒｓｓ２発現を阻害するための組成物、又は、コロナウィルス感染症の予防剤若しくは治療剤
JP6953047B1 (ja) * 2021-03-08 2021-10-27 株式会社 バイオミメティクスシンパシーズ アンジオテンシン転換酵素２（ａｃｅ２）及び／又はｔｍｐｒｓｓ２発現を阻害するための組成物

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015095650A1 (fr) * 2013-12-19 2015-06-25 Puretein Bioscience Llc. Méthodes de traitement d'un animal
JP2016065055A (ja) * 2014-09-19 2016-04-28 国立大学法人金沢大学 骨髄性白血病の治療剤
WO2020169707A1 (fr) * 2019-02-21 2020-08-27 INSERM (Institut National de la Santé et de la Recherche Médicale) Inhibiteur de foxo1 utilisé pour traiter des infections virales latentes
JP6906127B1 (ja) * 2021-01-29 2021-07-21 株式会社 バイオミメティクスシンパシーズ アンジオテンシン転換酵素２（ａｃｅ２）及び／若しくはｔｍｐｒｓｓ２発現を阻害するための組成物、又は、コロナウィルス感染症の予防剤若しくは治療剤
JP6953047B1 (ja) * 2021-03-08 2021-10-27 株式会社 バイオミメティクスシンパシーズ アンジオテンシン転換酵素２（ａｃｅ２）及び／又はｔｍｐｒｓｓ２発現を阻害するための組成物

Non-Patent Citations (11)

* Cited by examiner, † Cited by third party
Title
ALSAMMAN, A. M: "The transcriptomic profiling of SARS-CoV-2 compared to SARS, MERS, EBOV, and H1N1", PLOS ONE, 1 May 2020 (2020-05-01), pages 1 - 30, XP055955453, Retrieved from the Internet <URL:https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0243270> [retrieved on 20220826], DOI: 2020.05.06.080960 *
COUSELO‐SEIJAS MARINELA, ALMENGLÓ CRISTINA, AGRA‐BERMEJO ROSA, FERNANDEZ ÁNGEL, ALVAREZ EZEQUIEL, GONZÁLEZ‐JUANATEY JOSE, EIRAS SO: "Higher ACE2 expression levels in epicardial cells than subcutaneous stromal cells from patients with cardiovascular disease: Diabetes and obesity as possible enhancer", EUROPEAN JOURNAL OF CLINICAL INVESTIGATION, WILEY-BLACKWELL PUBLISHING LTD., GB, vol. 51, no. 5, 14 May 2021 (2021-05-14), GB , XP055955435, ISSN: 0014-2972, DOI: 10.1111/eci.13463 *
ESQUIVEL DIANA; MISHRA RANGNATH; SONI PRABHAT; SEETHARAMAN RAJASEKAR; MAHMOOD ANJUM; SRIVASTAVA ANAND: "Stem Cells Therapy as a Possible Therapeutic Option in Treating COVID-19 Patients", STEM CELL REVIEWS AND REPORTS, SPRINGER US, NEW YORK, vol. 17, no. 1, 1 January 1900 (1900-01-01), New York , pages 144 - 152, XP037374875, ISSN: 2629-3269, DOI: 10.1007/s12015-020-10017-6 *
FAN XIKANG; YIN CHENG; WANG JIAYU; YANG MINGJIA; MA HONGXIA; JIN GUANGFU; SONG MINGYANG; HU ZHIBIN; SHEN HONGBING; HANG DONG: "Pre-diagnostic circulating concentrations of insulin-like growth factor-1 and risk of COVID-19 mortality: results from UK Biobank", EUROPEAN JOURNAL OF EPIDEMIOLOGY, SPRINGER NETHERLANDS, DORDRECHT, vol. 36, no. 3, 1 January 1900 (1900-01-01), Dordrecht, pages 311 - 318, XP037418366, ISSN: 0393-2990, DOI: 10.1007/s10654-020-00709-1 *
JHA PRABHASH KUMAR, VIJAY AATIRA, HALU ARDA, UCHIDA SHIZUKA, AIKAWA MASANORI: "Gene Expression Profiling Reveals the Shared and Distinct Transcriptional Signatures in Human Lung Epithelial Cells Infected With SARS-CoV-2, MERS-CoV, or SARS-CoV: Potential Implications in Cardiovascular Complications of COVID-19", FRONTIERS IN CARDIOVASCULAR MEDICINE, vol. 7, 15 January 2021 (2021-01-15), XP055955452, DOI: 10.3389/fcvm.2020.623012 *
KALBHANDE DR JAYESH G, KALBHANDE G, DR VICKY, KULDEEP: "Use of Insulin in treatment of COVID-19: A proposal to explore feasibility", JOURNAL OF MEDICAL SCIENCE AND CLINICAL RESEARCH, vol. 08, no. 07, 31 July 2020 (2020-07-31), XP055955440, DOI: 10.18535/jmscr/v8i7.103 *
MISHRA DEVANSHI, DEY CHINMOY SANKAR: "Type-2 diabetes, a co-morbidity in Covid-19: does insulin signaling matter?", BIOCHEMICAL SOCIETY TRANSACTIONS, PORTLAND PRESS LTD, GB, vol. 49, no. 2, 30 April 2021 (2021-04-30), GB , pages 987 - 995, XP009538677, ISSN: 0300-5127, DOI: 10.1042/BST20201062 *
PEDERSEN KIM BRINT, CHODAVARAPU HARSHITA, LAZARTIGUES ERIC: "Forkhead Box Transcription Factors of the FOXA Class Are Required for Basal Transcription of Angiotensin-Converting Enzyme 2", JOURNAL OF THE ENDOCRINE SOCIETY, vol. 1, no. 4, 1 April 2017 (2017-04-01), pages 370 - 384, XP055955447, DOI: 10.1210/js.2016-1071 *
POCSFALVI GABRIELLA, MAMMADOVA RAMILA, RAMOS JUAREZ ANA PAULINA, BOKKA RAMESH, TREPICCIONE FRANCESCO, CAPASSO GIOVAMBATT: "COVID-19 and Extracellular Vesicles: An Intriguing Interplay", KIDNEY AND BLOOD PRESSURE RESEARCH, BASEL, CH, vol. 45, no. 5, 1 October 2020 (2020-10-01), CH , pages 661 - 670, XP055826579, ISSN: 1420-4096, DOI: 10.1159/000511402 *
ROCHA JOSé LUCAS MARTINS; DE OLIVEIRA WALDIR CéSAR FERREIRA; NORONHA NáDIA CáSSIA; DOS SANTOS NATALIA CRISTINE: "Mesenchymal Stromal Cells in Viral Infections: Implications for COVID-19", STEM CELL REVIEWS AND REPORTS, SPRINGER US, NEW YORK, vol. 17, no. 1, 1 January 1900 (1900-01-01), New York , pages 71 - 93, XP037374869, ISSN: 2629-3269, DOI: 10.1007/s12015-020-10032-7 *
SALEM ESAM S. B., GROBE NADJA, ELASED KHALID M.: "Insulin treatment attenuates renal ADAM17 and ACE2 shedding in diabetic Akita mice", AMERICAN JOURNAL OF PHYSIOLOGY: RENAL PHYSIOLOGY, AMERICAN PHYSIOLOGICAL SOCIETY, UNITED STATES, vol. 306, no. 6, 15 March 2014 (2014-03-15), United States , pages F629 - F639, XP055955437, ISSN: 1931-857X, DOI: 10.1152/ajprenal.00516.2013 *

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