WO2023147011A1 - Compositions et procédés d'inhibition du coronavirus 2 du syndrome respiratoire aigu sévère (sras) (sars-cov-2) - Google Patents

Compositions et procédés d'inhibition du coronavirus 2 du syndrome respiratoire aigu sévère (sras) (sars-cov-2) Download PDF

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Publication number
WO2023147011A1
WO2023147011A1 PCT/US2023/011690 US2023011690W WO2023147011A1 WO 2023147011 A1 WO2023147011 A1 WO 2023147011A1 US 2023011690 W US2023011690 W US 2023011690W WO 2023147011 A1 WO2023147011 A1 WO 2023147011A1
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inhibitor
plpro
sars
compound
ester
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PCT/US2023/011690
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English (en)
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Taval SHASHIDHARAMURTHY
Vicky MODY
Srujana Rayalam
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Vimu Therapeutics
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Publication of WO2023147011A1 publication Critical patent/WO2023147011A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
    • 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
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
    • 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
    • A61K31/65—Tetracyclines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/32—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C07C235/34—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/24—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring of the carbon skeleton
    • C07C237/26—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring of the carbon skeleton of a ring being part of a condensed ring system formed by at least four rings, e.g. tetracycline

Definitions

  • SARS-CoV-2 Severe Acute Respiratory Syndrome
  • the present invention relates to the field of virology. More specifically, the invention provides compositions and methods for the treatment, prevention, and/or inhibition of viral infections, particularly coronavirus infections such as SARS-CoV-2.
  • SARS-CoV Severe Acute Respiratory Syndrome coronavirus
  • MERS-CoV Middle East Respiratory Syndrome coronavirus
  • SARS-CoV-2 Severe Acute Respiratory Syndrome coronavirus-2 coronavirus-2
  • inhibitors of viral 3 -chymotrypsin like protease (3CLpro), papain like protease (PLpro), and/or RNA dependent RNA polymerase (RdRp) are provided.
  • the 3CLpro, PLpro, and/or RdRp are from a coronavirus, particularly SARS-CoV-2.
  • Compositions comprising a 3CLpro inhibitor, PLpro inhibitor, and/or RdRp inhibitor are also provided.
  • methods for treating, inhibiting, and/or preventing a viral infection, particularly a coronavirus infection or SARS- CoV-2 infection comprise administering a 3CLpro inhibitor, PLpro inhibitor, and/or RdRp inhibitor to a subject.
  • methods for inhibiting and/or reducing an activity of 3CLpro, PLpro, and/or RdRp are provided.
  • Figure 1 provides a graph of the inhibition of SARS-CoV-2 PLpro proteolytic activity by the indicated compounds.
  • DMSO dimethylsulfoxide (negative control).
  • GRL GRL0617 (positive control).
  • Figure 2 provides a graph of the inhibition of SARS-CoV-2 PLpro deubiquitinase (DUB) activity by the indicated compounds.
  • DMSO dimethylsulfoxide (negative control).
  • GRL GRL0617 (positive control).
  • Figure 3 provides graphs of the dose-dependent inhibition of SARS-CoV-2 PLpro proteolytic and DUB activity by minocycline-caffeic acid and 9-animo minocycline.
  • Figure 4 provides a graph of the inhibition of SARS-CoV-2 3CLpro proteolytic activity by the indicated compounds.
  • DMSO dimethylsulfoxide (negative control).
  • GC GC376 (positive control).
  • Figure 5 provides a graph of the inhibition of SARS-CoV-2 RdRp enzymatic activity by the indicated compounds.
  • DMSO dimethylsulfoxide (negative control).
  • EDTA ethylenediaminetetraacetic acid.
  • Figure 6 provides a graph of the inhibition of SARS-CoV-2 3CLpro proteolytic activity by the indicated compounds.
  • DMSO dimethylsulfoxide (negative control).
  • GC376 positive control.
  • Figure 7 provides graphs of the dose-dependent inhibition of SARS-CoV-2 3CLpro proteolytic activity by A- 1338152 and sabutoclax.
  • Figure 8 provides a graph of the inhibition of SARS-CoV-2 PLpro proteolytic activity by the indicated compounds.
  • DMSO dimethylsulfoxide (negative control).
  • GRL0617 positive control.
  • Figure 9 provides a graph showing the inhibition of SARS-CoV-2 replication (% reduction of viral load) and the cytotoxicity by the indicated compounds. Statistical significance is indicated.
  • RNA dependent RNA polymerase plays an indispensable role in synthesizing the new viral genome required for new virus formation.
  • the data presented herein shows that the small molecular weight molecules inhibit the enzymatic activity of PLpro, 3CLpro, and RdRp of SARS-CoV-2, thereby indicating therapeutic potential for inhibiting the replication of coronaviruses, particularly the SARS-CoV-2 virus to reduce the spread of COVID-19.
  • papain like protease (PLpro) inhibitors are provided.
  • the PLpro is a viral PLpro, particularly a coronavirus PLpro.
  • the PLpro is the SARS-CoV-2 PLpro.
  • the PLpro inhibitor may inhibit the protease activity and/or deubiquitinase activity of PLpro.
  • the PLpro inhibitor is a compound from Table 1 or a pharmaceutically acceptable salt, stereoisomer, solvate, and/or ester thereof. In certain embodiments, the PLpro inhibitor is minocycline with a substitution at position 9 or a pharmaceutically acceptable salt, stereoisomer, solvate, and/or ester thereof. In certain embodiments, the PLpro inhibitor has the formula:
  • R, Ri, R2, R’, R”, and/or R’ are optionally substituted (e.g., with halo, haloalkyl, hydroxyl, thiol, methoxy, carboxyl, amino, nitro, nitrile, carbamoyl, urea, ester, or thioester).
  • R is NR1R2. In certain embodiments, at least one of Ri and R2 is hydrogen.
  • Ri is hydrogen.
  • R2 is an optionally substituted aryl, arylalkyl, heteroaryl, heteroarylalkyl, carbocyclyl, carbocyclylalkyl, heterocyclyl, or heterocyclylalkyl.
  • minocycline may be depicted as application to encompass all chemical structures of minocycline.
  • the PLpro inhibitor is minocycline-caffeic acid or a pharmaceutically acceptable salt, stereoisomer, solvate, and/or ester thereof. In certain embodiments, the PLpro inhibitor is or a pharmaceutically acceptable salt, stereoisomer, solvate, and/or ester thereof.
  • the PLpro inhibitor is 9-amino-minocycline or a pharmaceutically acceptable salt, stereoisomer, solvate, and/or ester thereof. In certain embodiments, the PLpro inhibitor is or a pharmaceutically acceptable salt, stereoisomer, solvate, and/or ester thereof. In certain embodiments, the PLpro inhibitor is a Bcl2 (B-cell lymphoma 2) inhibitor.
  • the PLpro inhibitor is a compound from Table 3 or a pharmaceutically acceptable salt, stereoisomer, solvate, and/or ester thereof. In certain embodiments, the PLpro inhibitor is sabutoclax or a pharmaceutically acceptable salt, stereoisomer, solvate, and/or ester thereof. In certain embodiments, the PLpro inhibitor is A- 1331852 or a pharmaceutically acceptable salt, stereoisomer, solvate, and/or ester thereof. In certain embodiments, the PLpro inhibitor is or a pharmaceutically acceptable salt, stereoisomer, solvate, and/or ester thereof.
  • the PLpro inhibitor is or a pharmaceutically acceptable salt, stereoisomer, solvate, and/or ester thereof.
  • the instant invention also encompasses compositions comprising a PLpro inhibitor.
  • the composition further comprises a pharmaceutical carrier.
  • the composition further comprises another therapeutic agent, such as a therapeutic agent for the treatment, prevention, and/or inhibition of coronavirus, particularly SARS-CoV-2.
  • the composition further comprises a 3CLpro inhibitor and/or RdRp inhibitor.
  • the instant invention also encompasses method of inhibiting and/or reducing an activity of PLpro.
  • the method comprises contacting PLpro with a PLpro inhibitor of the instant invention.
  • the method is in vitro.
  • the method comprises contacting a cell (e.g., a cell infected with a coronavirus, particularly SARS-CoV-2) with a PLpro inhibitor.
  • RNA dependent RNA polymerase (RdRp) inhibitors are provided.
  • the RdRp is a viral RdRp, particularly a coronavirus RdRp.
  • the RdRp is the SARS-CoV-2 RdRp.
  • the RdRp inhibitor inhibits the polymerase activity of RdRp.
  • the RdRp inhibitor is a compound from Table 1 or a pharmaceutically acceptable salt, stereoisomer, solvate, and/or ester thereof.
  • the RdRp inhibitor comprises phenylalanine-caffeic acid or a pharmaceutically acceptable salt, stereoisomer, solvate, and/or ester thereof.
  • the RdRp inhibitor has the formula: wherein R, Ri, R2, R3, R4, and R5 are independently selected from the group consisting of H, halo, haloalkyl (e.g., alkyl (e.g., methyl) substituted with one or more halogens (e.g., CCI3 or CF 3 )), alkyl (e.g., C1-C5 or C1-C3), alkenyl (e.g., C2-C5 or C2-C3), alkylthio (-S-alkyl (e.g., C1-C5 or C1-C3)), alkoxyl (-O-alkyl (e.g., C1-C5 or C1-C3)), hydroxyl (-OH), thiol (-SH), methoxy (-O-CH3), carboxyl (-COOH), amino (-NH2), nitro (-NO2), nitrile (-CN), carbamoyl (e.g.
  • R, Ri, R2, R3, R4, R’, R”, and/or R’ are optionally substituted (e.g., with halo, haloalkyl, hydroxyl, thiol, methoxy, carboxyl, amino, nitro, nitrile, carbamoyl, urea, ester, or thioester).
  • at least one of R4 and R5 is -OH.
  • R4 and R5 are -OH.
  • R3 is -COOH.
  • R is H.
  • n 1.
  • R2 is H or - OH.
  • at least one of Ri and R2 is -OH.
  • Ri and R2 are -OH.
  • R, Ri, R2, R4, and R5 are -OH and, optionally, R3 is H.
  • the RdRp inhibitor has the formula: wherein R, R3, and R4 are independently selected from the group consisting of H, halo, haloalkyl (e.g., alkyl (e.g., methyl) substituted with one or more halogens (e.g., CCI3 or CF 3 )), alkyl (e.g., C1-C5 or C1-C3), alkenyl (e.g., C2-C5 or C2-C3), alkylthio (-S-alkyl (e.g., C1-C5 or C1-C3)), alkoxyl (-O-alkyl (e.g., C1-C5 or C1-C3)), hydroxyl (-OH), thiol (-SH), methoxy (-O-CH3), carboxyl (-COOH), amino (-NH2), nitro (-NO2), nitrile (-CN), carbamoyl (e.g., haloalky
  • R, R3, R4, R’, R”, and/or R’ are optionally substituted (e.g., with halo, haloalkyl, hydroxyl, thiol, methoxy, carboxyl, amino, nitro, nitrile, carbamoyl, urea, ester, or thioester).
  • R is NO2.
  • at least one of R3 and R4 is -OH.
  • R3 and R4 are -OH.
  • the RdRp inhibitor is 4-nitro-phenylalanine-caffeic acid or a pharmaceutically acceptable salt, stereoisomer, solvate, and/or ester thereof.
  • the RdRp inhibitor is or a pharmaceutically acceptable salt, stereoisomer, solvate, and/or ester thereof.
  • the RdRp inhibitor is a caffeic acid-amino acid derivative or a pharmaceutically acceptable salt, stereoisomer, solvate, and/or ester thereof. In certain embodiments, the RdRp inhibitor is caffeic acid-norepinephrine or a pharmaceutically acceptable salt, stereoisomer, solvate, and/or ester thereof.
  • compositions comprising a RdRp inhibitor.
  • the composition further comprises a pharmaceutical carrier.
  • the composition further comprises another therapeutic agent, such as a therapeutic agent for the treatment, prevention, and/or inhibition of coronavirus, particularly SARS-CoV-2.
  • the composition further comprises a 3CLpro inhibitor and/or PLpro inhibitor.
  • the RdRp inhibitor of the composition further comprising a 3CLpro inhibitor and/or PLpro inhibitor, is a caffeic acid- amino acid derivative or a pharmaceutically acceptable salt, stereoisomer, solvate, and/or ester thereof.
  • the instant invention also encompasses method of inhibiting and/or reducing an activity of RdRp.
  • the method comprises contacting RdRp with a RdRp inhibitor of the instant invention.
  • the method is in vitro.
  • the method comprises contacting a cell (e.g., a cell infected with a coronavirus, particularly SARS-CoV-2) with a RdRp inhibitor.
  • 3 -chymotrypsin like protease (3CLpro) inhibitors are provided.
  • the 3CLpro is a viral 3CLpro, particularly a coronavirus 3CLpro.
  • the 3CLpro is the SARS-CoV-2 3CLpro.
  • the 3CLpro inhibitor inhibits the protease activity of 3CLpro.
  • the 3CLpro inhibitor is a Bcl2 (B-cell lymphoma 2) inhibitor. In certain embodiments, the 3CLpro inhibitor is a compound from Table 3. In certain embodiments, the 3CLpro inhibitor is sabutoclax. In certain embodiments, the 3CLpro inhibitor is A-1331852. In certain embodiments, the 3CLpro inhibitor is
  • the 3CLpro inhibitor is The instant invention also encompasses compositions comprising a 3CLpro inhibitor.
  • the composition further comprises a pharmaceutical carrier.
  • the composition further comprises another therapeutic agent, such as a therapeutic agent for the treatment, prevention, and/or inhibition of coronavirus, particularly SARS-CoV-2.
  • the composition further comprises a PLpro inhibitor and/or RdRp inhibitor.
  • the instant invention also encompasses method of inhibiting and/or reducing an activity of 3CLpro.
  • the method comprises contacting 3CLpro with a 3CLpro inhibitor of the instant invention.
  • the method is in vitro.
  • the method comprises contacting a cell (e.g., a cell infected with a coronavirus, particularly SARS-CoV-2) with a 3CLpro inhibitor.
  • the viral infection is a coronavirus infection.
  • coronaviruses include, without limitation, SARS-CoV, MERS-CoV, SARS-CoV-2, and animal coronaviruses such as FCoV.
  • the coronavirus infection is a SARS-CoV-2 infection.
  • the methods of the instant invention comprise administering a 3CLpro inhibitor, PLpro inhibitor, and/or RdRp inhibitor to a subject in need thereof. In certain embodiments, the methods comprise administering a 3CLpro inhibitor and PLpro inhibitor to a subject in need thereof.
  • the methods comprise administering a 3CLpro inhibitor and RdRp inhibitor to a subject in need thereof. In certain embodiments, the methods comprise administering a RdRp inhibitor and PLpro inhibitor to a subject in need thereof. In certain embodiments, the methods comprise administering a 3CLpro inhibitor, RdRp inhibitor, and PLpro inhibitor to a subject in need thereof. In certain embodiments, the methods comprise administering sabutoclax, 4-nitro-phenylalanine-caffeic acid, minocycline-caffeic acid, and/or 9-amino- minocy cline (or any combination thereof) to a subject in need thereof.
  • the methods comprise administering sabutoclax, 4-nitro-phenylalanine-caffeic acid, and/or 9-amino-minocy cline to a subject in need thereof. In certain embodiments, the methods comprise administering sabutoclax, 4-nitro-phenylalanine-caffeic acid, and/or minocycline-caffeic acid to a subject in need thereof. In certain embodiments, the methods comprise administering 4-nitro-phenylalanine-caffeic acid, minocycline-caffeic acid, and/or 9-amino-minocy cline to a subject in need thereof.
  • the methods comprise administering at least one compound of formula (I), (II), and/or (III) to the subject.
  • methods of treating, preventing, and/or inhibiting cancer and/or reducing tumor growth in a subject are provided.
  • the methods of the instant invention comprise administering a 3CLpro inhibitor, PLpro inhibitor, and/or RdRp inhibitor to a subject in need thereof.
  • the methods comprise administering a 3CLpro inhibitor and PLpro inhibitor to a subject in need thereof.
  • the methods comprise administering a 3CLpro inhibitor and RdRp inhibitor to a subject in need thereof.
  • the methods comprise administering a RdRp inhibitor and PLpro inhibitor to a subject in need thereof. In certain embodiments, the methods comprise administering a 3CLpro inhibitor, RdRp inhibitor, and PLpro inhibitor to a subject in need thereof. In certain embodiments, the methods comprise administering sabutoclax, 4-nitro-phenylalanine-caffeic acid, minocycline-caffeic acid, and/or 9-amino-minocy cline (or any combination thereof) to a subject in need thereof.
  • the methods comprise administering sabutoclax, 4-nitro-phenylalanine- caffeic acid, and/or 9-amino-minocy cline to a subject in need thereof. In certain embodiments, the methods comprise administering sabutoclax, 4-nitro-phenylalanine-caffeic acid, and/or minocycline-caffeic acid to a subject in need thereof. In certain embodiments, the methods comprise administering 4-nitro-phenylalanine-caffeic acid, minocycline-caffeic acid, and/or 9-amino-minocy cline to a subject in need thereof. In certain embodiments, the methods comprise administering at least one compound of formula (I), (II), and/or (III) to the subject.
  • methods of treating, preventing, and/or inhibiting inflammation in a subject comprise administering a 3CLpro inhibitor, PLpro inhibitor, and/or RdRp inhibitor to a subject in need thereof.
  • the methods comprise administering a 3CLpro inhibitor and PLpro inhibitor to a subject in need thereof.
  • the methods comprise administering a 3CLpro inhibitor and RdRp inhibitor to a subject in need thereof.
  • the methods comprise administering a RdRp inhibitor and PLpro inhibitor to a subject in need thereof.
  • the methods comprise administering a 3CLpro inhibitor, RdRp inhibitor, and PLpro inhibitor to a subject in need thereof.
  • the methods comprise administering sabutoclax, 4-nitro-phenylalanine-caffeic acid, minocycline-caffeic acid, and/or 9-amino- minocy cline (or any combination thereof) to a subject in need thereof.
  • the methods comprise administering sabutoclax, 4-nitro-phenylalanine-caffeic acid, and/or 9-amino-minocy cline to a subject in need thereof.
  • the methods comprise administering sabutoclax, 4-nitro-phenylalanine-caffeic acid, and/or minocycline-caffeic acid to a subject in need thereof. In certain embodiments, the methods comprise administering 4-nitro-phenylalanine-caffeic acid, minocycline-caffeic acid, and/or 9-amino-minocy cline to a subject in need thereof. In certain embodiments, the methods comprise administering at least one compound of formula (I), (II), and/or (III) to the subject.
  • methods of treating, preventing, and/or inhibiting a metabolic disorder in a subject comprise administering a 3CLpro inhibitor, PLpro inhibitor, and/or RdRp inhibitor to a subject in need thereof.
  • the methods comprise administering a 3CLpro inhibitor and PLpro inhibitor to a subject in need thereof.
  • the methods comprise administering a 3CLpro inhibitor and RdRp inhibitor to a subject in need thereof.
  • the methods comprise administering a RdRp inhibitor and PLpro inhibitor to a subject in need thereof.
  • the methods comprise administering a 3CLpro inhibitor, RdRp inhibitor, and PLpro inhibitor to a subject in need thereof.
  • the methods comprise administering sabutoclax, 4-nitro-phenylalanine-caffeic acid, minocycline-caffeic acid, and/or 9-amino- minocy cline (or any combination thereof) to a subject in need thereof.
  • the methods comprise administering sabutoclax, 4-nitro-phenylalanine-caffeic acid, and/or 9-amino-minocy cline to a subject in need thereof.
  • the methods comprise administering sabutoclax, 4-nitro-phenylalanine-caffeic acid, and/or minocycline-caffeic acid to a subject in need thereof. In certain embodiments, the methods comprise administering 4-nitro-phenylalanine-caffeic acid, minocycline-caffeic acid, and/or 9-amino-minocy cline to a subject in need thereof. In certain embodiments, the methods comprise administering at least one compound of formula (I), (II), and/or (III) to the subject.
  • methods of treating, preventing, and/or inhibiting asthma in a subject comprise administering a 3CLpro inhibitor, PLpro inhibitor, and/or RdRp inhibitor to a subject in need thereof.
  • the methods comprise administering a 3CLpro inhibitor and PLpro inhibitor to a subject in need thereof.
  • the methods comprise administering a 3CLpro inhibitor and RdRp inhibitor to a subject in need thereof.
  • the methods comprise administering a RdRp inhibitor and PLpro inhibitor to a subject in need thereof.
  • the methods comprise administering a 3CLpro inhibitor, RdRp inhibitor, and PLpro inhibitor to a subject in need thereof.
  • the methods comprise administering sabutoclax, 4- nitro-phenylalanine-caffeic acid, minocycline-caffeic acid, and/or 9-amino-minocycline (or any combination thereof) to a subject in need thereof.
  • the methods comprise administering sabutoclax, 4-nitro-phenylalanine-caffeic acid, and/or 9-amino- minocycline to a subject in need thereof.
  • the methods comprise administering sabutoclax, 4-nitro-phenylalanine-caffeic acid, and/or minocycline-caffeic acid to a subject in need thereof. In certain embodiments, the methods comprise administering 4- nitro-phenylalanine-caffeic acid, minocycline-caffeic acid, and/or 9-amino-minocycline to a subject in need thereof. In certain embodiments, the methods comprise administering at least one compound of formula (I), (II), and/or (III) to the subject. In certain embodiments, the compound comprises caffeic Acid-norepinephrine.
  • compositions and methods of the instant invention may further comprise an additional therapeutic agent, particularly an antiviral agent, particularly a therapeutic agent for a coronavirus or SARS-CoV-2 infection.
  • the additional therapeutic agent is a coronavirus or SARS-CoV-2 vaccine (e.g., from Pfizer- BioNTech, Moderna, or Johnson & Johnson).
  • examples of other therapeutic agents include, without limitation, remdesivir and PaxlovidTM (nirmatrelvir and ritonavir).
  • the agents can be administered at the same time (e.g., simultaneously) and/or at different times (e.g., sequentially).
  • the agents may be administered in a single composition (e.g., with a pharmaceutically acceptable carrier) or in more than one composition (e.g., each agent may be contained within a separate composition with a pharmaceutically acceptable carrier, optionally the same or different carrier).
  • a single compound can serve as more than one inhibitor.
  • A-1331852 can be administered as a 3CLpro inhibitor and a PLpro inhibitor.
  • A-1331852 can be administered with an RdRp inhibitor to effectively inhibit 3CLpro, PLpro, and RdRp.
  • A-1331852 can be administered in combination with a stronger 3CLpro inhibitor and/or PLpro inhibitor.
  • A-1331852 can be administered with the PLpro inhibitor minocycline-caffeic acid or 9-amino-minocycline, optionally with a RdRp inhibitor.
  • the compounds of the instant invention can be administered to an animal, in particular a mammal, more particularly a human, in order to treat, inhibit, and/or prevent a viral infection, particularly a coronavirus infection, particularly SARS-CoV-2.
  • the pharmaceutical compositions of the instant invention may also comprise at least one other therapeutic agent such as an antiviral agent, particularly at least one other anti-coronavirus or anti-SARS-CoV-2 compound or agent.
  • the additional therapeutic agent may also be administered in a separate pharmaceutical composition from the prodrugs or compositions of the instant invention.
  • the pharmaceutical compositions may be administered at the same time or at different times (e.g., sequentially).
  • the dosage ranges for the administration of the compounds and/or compositions of the invention are those large enough to produce the desired effect (e.g., curing, relieving, treating, and/or preventing the viral infection, the symptoms of it, or the predisposition towards it).
  • the dosage should not be so large as to cause significant adverse side effects, such as unwanted cross-reactions, anaphylactic reactions, and the like.
  • the dose and dosage regimen will vary with the age, condition, sex, weight, and extent of the disease in the patient and can be determined by one of skill in the art.
  • the physician may also take into account the route of administration, the pharmaceutical carrier, and the compound’s biological activity.
  • the dosage can be adjusted by the individual physician in the event of any counter indications.
  • the compounds described herein will generally be administered to a patient as a pharmaceutical composition.
  • patient refers to human or animal subjects. These compounds may be employed therapeutically, under the guidance of a physician or veterinarian.
  • compositions comprising the compounds of the instant invention may be conveniently formulated for administration with any pharmaceutically acceptable carrier(s).
  • the compounds may be formulated with an acceptable medium such as water, buffered saline, ethanol, polyol (for example, glycerol, propylene glycol, liquid polyethylene glycol and the like), dimethyl sulfoxide (DMSO), oils, detergents, suspending agents, or suitable mixtures thereof, particularly an aqueous solution.
  • concentration of the compounds in the chosen medium may be varied and the medium may be chosen based on the desired route of administration of the pharmaceutical composition. Except insofar as any conventional media or agent is incompatible with the compounds to be administered, its use in the pharmaceutical composition is contemplated.
  • a suitable pharmaceutical composition will also depend upon the mode of administration chosen.
  • the compounds of the invention may be administered by direct injection or intravenously.
  • a pharmaceutical composition comprises the compound dispersed in a medium that is compatible with the site of injection.
  • the compounds of the instant invention may be administered by any method.
  • the compounds of the instant invention can be administered, without limitation parenterally, subcutaneously, orally, by inhalation, nasally, topically, pulmonarily, rectally, vaginally, intravenously, intraperitoneally, intradermally, intrathecally, intracerbrally, epidurally, intramuscularly, intradermally, or intracarotidly.
  • the compound is administered parenterally.
  • the compound is administered orally, intramuscularly, subcutaneously, or to the bloodstream (e.g., intravenously).
  • the compound is administered intramuscularly or subcutaneously.
  • the compound is administered nasally (e.g., by nasal spray, nasal powder, or nasal drops).
  • the compound is administered by inhalation.
  • compositions for injection are known in the art. If injection is selected as a method for administering the compound(s), steps must be taken to ensure that sufficient amounts of the molecules reach their target cells to exert a biological effect.
  • Dosage forms for oral administration include, without limitation, tablets (e.g., coated and uncoated, chewable), gelatin capsules (e.g., soft or hard), lozenges, troches, solutions, emulsions, suspensions, syrups, elixirs, powders/granules (e.g., reconstitutable or dispersible) gums, and effervescent tablets.
  • Dosage forms for parenteral administration include, without limitation, solutions, emulsions, suspensions, dispersions and powders/granules for reconstitution.
  • Dosage forms for topical administration include, without limitation, creams, gels, ointments, salves, patches and transdermal delivery systems.
  • compositions containing a compound of the present invention as the active ingredient in intimate admixture with a pharmaceutically acceptable carrier can be prepared according to conventional pharmaceutical compounding techniques.
  • the carrier may take a wide variety of forms depending on the form of pharmaceutical composition desired for administration, e.g., intravenous, subcutaneous, oral, inhalation, or direct injection.
  • the compounds may also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and/or multilamellar vesicles.
  • the compound(s) of the instant invention may be contained within or be encapsulated by the liposome delivery system.
  • Liposomes may comprise a variety of phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines.
  • Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid.
  • the liposome delivery system may be targeted to desired cells (e.g., infected cells) such as by targeting ACE2 (e.g., with an anti-ACE2 antibody, particularly to the extracellular domain of ACE2) or a coronavirus spike (S) glycoprotein (e.g., with an anti-spike (S) glycoprotein antibody, particularly to the extracellular domain of spike (S) glycoprotein).
  • ACE2 e.g., with an anti-ACE2 antibody, particularly to the extracellular domain of ACE2
  • S coronavirus spike
  • the liposomes may be conjugated (e.g., directly or via a linker) to an ACE2 binding moiety (e.g., an anti-ACE2 antibody) or a spike (S) glycoprotein binding moiety (e.g., an anti-spike (S) glycoprotein antibody).
  • Liposomal suspensions or delivery systems can also be used as pharmaceutically acceptable carriers.
  • the compounds of the instant invention may also be administered within nanoparticles or nanocarriers.
  • the compound(s) of the instant invention may be contained within or be encapsulated by the nanoparticles or nanocarriers.
  • Nanoparticles or nanocarriers may comprise biodegradable, biocompatible polymers.
  • the nanoparticles or nanocarriers may be targeted to desired cells (e.g., infected cells) such as by targeting ACE2 (e.g., with an anti-ACE2 antibody, particularly to the extracellular domain of ACE2) or a coronavirus spike (S) glycoprotein (e.g., with an anti-spike (S) glycoprotein antibody, particularly to the extracellular domain of spike (S) glycoprotein).
  • nanoparticles or nanocarriers may be conjugated (e.g., directly or via a linker) to an ACE2 binding moiety (e.g., an anti-ACE2 antibody)or a spike (S) glycoprotein binding moiety (e.g., an anti-spike (S) glycoprotein antibody).
  • ACE2 binding moiety e.g., an anti-ACE2 antibody
  • S spike glycoprotein binding moiety
  • Nanoparticles or nanocarriers may be contained within a pharmaceutically acceptable carrier.
  • the compounds of the instant invention may also be targeted to desired cells (e.g., infected cells) such as by targeting ACE2 (e.g., with an anti-ACE2 antibody, particularly to the extracellular domain of ACE2) or a coronavirus spike (S) glycoprotein (e.g., with an antispike (S) glycoprotein antibody, particularly to the extracellular domain of spike (S) glycoprotein).
  • ACE2 e.g., with an anti-ACE2 antibody, particularly to the extracellular domain of ACE2
  • S coronavirus spike
  • S coronavirus spike
  • the compounds may be conjugated (e.g., directly or via a linker) to an ACE2 binding moiety (e.g., an anti-ACE2 antibody) or a spike (S) glycoprotein binding moiety (e.g., an anti-spike (S) glycoprotein antibody).
  • the compounds may be administered by inhalation.
  • the inhaled compounds or compositions are formulated in the form of a spray, an aerosol spray, such as one generated from a pressured container or dispenser that contains a suitable propellant (e.g., a gas such as carbon dioxide, a C3-C5 alkane (propane, butane, or heptane), a hydrogen-containing fluorocarbon propellant, or mixtures thereof), or a nebulizer.
  • a suitable propellant e.g., a gas such as carbon dioxide, a C3-C5 alkane (propane, butane, or heptane), a hydrogen-containing fluorocarbon propellant, or mixtures thereof
  • a suitable propellant e.g., a gas such as carbon dioxide, a C3-C5 alkane (propane, butane, or heptane), a hydrogen-containing fluorocarbon propellant, or mixtures thereof
  • a pharmaceutical composition of the invention may be formulated in dosage unit form for ease of administration and uniformity of dosage.
  • Dosage unit form refers to a physically discrete unit of the pharmaceutical composition appropriate for the patient undergoing treatment. Each dosage should contain a quantity of active ingredient calculated to produce the desired effect in association with the selected pharmaceutical carrier. Procedures for determining the appropriate dosage unit are well known to those skilled in the art.
  • the appropriate dosage unit for the administration of compounds may be determined by evaluating the toxicity of the molecules or cells in animal models. Various concentrations of compounds in pharmaceutical composition may be administered to mice, and the minimal and maximal dosages may be determined based on the beneficial results and side effects observed as a result of the treatment. Appropriate dosage unit may also be determined by assessing the efficacy of the treatment in combination with other standard drugs. The dosage units of compound may be determined individually or in combination with each treatment according to the effect detected.
  • the pharmaceutical composition comprising the compound(s) may be administered at appropriate intervals until the pathological symptoms are reduced or alleviated, after which the dosage may be reduced to a maintenance level.
  • the appropriate interval in a particular case would normally depend on the condition of the patient.
  • the instant also encompasses delivering the compound(s) of the instant invention to a cell in vitro (e.g., in culture).
  • the compound may be delivered to the cell in a composition comprising at least one carrier.
  • In vitro methods of inhibiting PLpro, 3CLpro, and/or RdRp are also encompassed by the instant invention.
  • the in vitro methods comprise contacting the enzymes (e.g., in solution) or cells comprising the enzymes with a compound(s) of the instant invention.
  • isolated is not meant to exclude artificial or synthetic mixtures with other compounds or materials, or the presence of impurities that do not interfere with the fundamental activity, and that may be present, for example, due to incomplete purification, or the addition of stabilizers.
  • substantially pure refers to a preparation comprising at least 50-60% by weight of a given material (e.g., nucleic acid, oligonucleotide, protein, etc.). Particularly, the preparation comprises at least 75% by weight, at least 80% by weight, at least 90% by weight, or at least 95% or more by weight of the given compound. Purity may be measured by methods appropriate for the given compound (e.g. chromatographic methods, agarose or polyacrylamide gel electrophoresis, HPLC analysis, and the like).
  • “Pharmaceutically acceptable” indicates approval by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.
  • a “carrier” refers to, for example, a diluent, adjuvant, preservative (e.g., Thimersol, benzyl alcohol), anti-oxidant (e.g., ascorbic acid, sodium metabisulfite), solubilizer (e.g., TweenTM 80, polysorbate 80), emulsifier, buffer (e.g., Tris HC1, acetate, phosphate), antimicrobial, bulking substance (e.g., lactose, mannitol), excipient, auxiliary agent or vehicle with which an active agent of the present invention is administered.
  • Pharmaceutically acceptable carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin.
  • Water or aqueous saline solutions and aqueous dextrose and glycerol solutions are preferably employed as carriers, particularly for injectable solutions.
  • Suitable pharmaceutical carriers are described in “Remington's Pharmaceutical Sciences” by E.W. Martin (Mack Publishing Co., Easton, PA); Gennaro, A. R., Remington: The Science and Practice of Pharmacy (Lippincott, Williams and Wilkins); Liberman, et al., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York; and Kibbe, et al., Eds., Handbook of Pharmaceutical Excipients, American Pharmaceutical Association, Washington.
  • treat refers to any type of treatment that imparts a benefit to a patient afflicted with a disease, including improvement in the condition of the patient (e.g., in one or more symptoms), delay in the progression of the condition, etc.
  • the term “prevent” refers to the prophylactic treatment of a subject who is at risk of developing a condition (e.g., viral infection) resulting in a decrease in the probability that the subject will develop the condition.
  • a condition e.g., viral infection
  • a “therapeutically effective amount” of a compound or a pharmaceutical composition refers to an amount effective to prevent, inhibit, treat, and/or lessen the symptoms of a particular disorder or disease.
  • the treatment of a viral infection herein may refer to an amount sufficient to inhibit viral replication and/or inhibiting, treating, relieving, and/or preventing the viral infection, the symptom of it, or the predisposition towards it.
  • an antiviral refers to a substance that destroys a virus and/or suppresses replication (reproduction) of the virus.
  • an antiviral may inhibit and or prevent: production of viral particles, maturation of viral particles, viral attachment, viral uptake into cells, viral assembly, viral release/budding, and/or viral integration.
  • therapeutic agent refers to a chemical compound or biological molecule including, without limitation, nucleic acids, peptides, proteins, and antibodies that can be used to treat a condition, disease, or disorder or reduce the symptoms of the condition, disease, or disorder.
  • small molecule refers to a substance or compound that has a relatively low molecular weight (e.g., less than 4,000, less than 2,000, particularly less than 1 kDa).
  • small molecules are organic, but are not proteins, polypeptides, or nucleic acids, though they may be amino acids or dipeptides.
  • alkyl refers to a saturated linear or branched-chain monovalent hydrocarbon radical.
  • the alkyl refers to linear or branched C1-C32 alkyl, C1-C24 alkyl, C1-C12 alkyl, C1-C8 alkyl, C1-C6 alkyl, C1-C5 alkyl, C1-C4 alkyl, or C1-C3 alkyl.
  • an alkyl refers to a linear or branched C1-C6 alkyl, C1-C5 alkyl, C1-C4 alkyl, or C1-C3 alkyl.
  • alkyl groups include methyl, ethyl, 1 -propyl, 2-propyl, i-propyl, 1 -butyl, 2 -m ethyl- 1 -propyl, 2-butyl, 2- methyl-2-propyl, 1 -pentyl, n-pentyl, 2-pentyl, 3 -pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3 -methyl- 1 -butyl, 2-methyl-l -butyl, 1 -hexyl, 2-hexyl, 3 -hexyl, 2-methyl-2-pentyl, 3-methyl- 2-pentyl, 4-methyl-2-pentyl, 3 -methyl-3 -pentyl, 2-methyl-3 -pentyl, 2,3-dimethyl-2-butyl, 3,3- dimethyl-2 -butyl, heptyl, octyl, nonyl, dec
  • an alkyl group is a C1-C6 alkyl group. In some embodiments, an alkyl group is a C1-C3 alkyl group. In some embodiments, an alkyl group is a C1-C2 alkyl group.
  • heteroalkyl refers to an alkyl or alkenyl wherein one or more (e.g., 1, 2, 3, or 4) carbon atoms have been replaced with a heteroatom (e.g., O, N, or S; (nitrogen or sulfur heteroatoms may optionally be oxidized (e.g., NO, SO, SO2)).
  • a heteroatom e.g., O, N, or S
  • nitrogen or sulfur heteroatoms may optionally be oxidized (e.g., NO, SO, SO2)
  • alkenyl refers to an unsaturated linear or branched-chain monovalent hydrocarbon radical.
  • the alkenyl refers to linear or branched C2-C32 alkenyl, C2-C24 alkenyl, C2-C12 alkenyl, C2-C8 alkenyl, C2-C6 alkenyl, C2-C5 alkenyl, C2-C4 alkenyl, or C2-C3 alkenyl.
  • an alkenyl refers to linear or branched C2-C6 alkenyl, C2-C5 alkenyl, C2-C4 alkenyl, or C2-C3 alkenyl.
  • an alkenyl group is a C2-C3 alkenyl group.
  • carbocyclic refers to a group that comprises a saturated, partially unsaturated, or aromatic ring system having 3 to 20 carbon atoms.
  • the carbocyclic group may be part of a larger moiety (e.g., an alkcarbocyclic group).
  • the term carbocyclic includes mono-, bi-, tri-, fused, bridged, and spiro-ring systems, and combinations thereof.
  • a carbocyclic includes 3 to 15 carbon atoms (C3-C15).
  • a carbocyclic includes 3 to 12 carbon atoms (C3-C12).
  • a carbocyclic includes C3-C8, C3-C10, C5-C10, C3-C8, C3-C6 or C5-C6.
  • a carbocyclic is bicyclic and includes C7-C12.
  • the term carbocyclic includes aryl ring systems.
  • the term carbocyclic also includes cycloalkyl rings (e.g., saturated or partially unsaturated mono-, bi-, or spiro-carbocycles).
  • carbocyclic also includes a carbocyclic ring fused to one or more (e.g., 1, 2 or 3) different cyclic groups (e.g., aryl or heterocyclic rings), optionally where the radical or point of attachment is on the carbocyclic ring.
  • cyclic groups e.g., aryl or heterocyclic rings
  • Carbocyclylalkyl refers to a group of the formula -X- carbocyclic, where X is an alkyl (alkylene) or alkenyl chain.
  • heterocyclic or “heterocyclyl” refers to a carbocyclic wherein one or more (e.g., 1, 2, 3, or 4) carbon atoms have been replaced with a heteroatom (e.g., O, N, or S; (nitrogen or sulfur heteroatoms may optionally be oxidized (e.g., NO, SO, SO 2 )).
  • a heteroatom e.g., O, N, or S
  • nitrogen or sulfur heteroatoms may optionally be oxidized (e.g., NO, SO, SO 2 )).
  • heterocyclylalkyl refers to a group of the formula -X- heterocyclic, where X is an alkyl (alkylene) or alkenyl chain.
  • aryl refers to monocyclic and bicyclic aromatic groups.
  • the aryl may contain 6 to 10 carbons in the ring portion.
  • arylalkyl refers to a group of the formula -X-aryl, where X is an alkyl (alkylene) chain.
  • heteroaryl refers to an aryl wherein one or more (e.g., 1, 2, 3, or 4) carbon atoms have been replaced with a heteroatom (e.g., O, N, or S; (nitrogen or sulfur heteroatoms may optionally be oxidized (e.g., NO, SO, SO 2 )).
  • a heteroatom e.g., O, N, or S
  • nitrogen or sulfur heteroatoms may optionally be oxidized (e.g., NO, SO, SO 2 )).
  • heteroarylalkyl refers to a group of the formula -X- heteroaryl, where X is an alkyl (alkylene) or alkenyl chain.
  • halogen refers to fluorine, chlorine, bromine, or iodine.
  • solvate refers to a complex of variable stoichiometry formed by a solute (e.g., a compound of the present invention) and a solvent, particularly water. Such solvents, for the purpose of the invention, should not interfere with the biological activity of the solute.
  • suitable solvents include, but are not limited to water, methanol, ethanol, and acetic acid.
  • the solvent may be a pharmaceutically acceptable solvent.
  • the solvate of the compounds described herein may include, but not limited to, hemihydrate, monohydrate, or trihydrate etc.
  • Coronaviruses belong to family Coronaviridae and subfamily Coronavirinae with single stranded RNA as their genetic material. Based on their genetic and infectious criteria, they are classified as a-CoVs, P-CoVs, and y-CoVs (van Regenmortel, et al. (2000) Coronaviridae. hr.
  • Virus taxonomy Classification and nomenclature of viruses Seventh report of the International Committee on Taxonomy of Viruses, Academic Press, San Diego).
  • CoVs were identified as infectious agents of birds and mammals that cause severe respiratory tract infection (Lee, C. (2015) Virol. J., 12: 193; Bande, et al. (2015) J. Immunol. Res., 2015:424860).
  • Recently, some CoVs surpassed the cross-species barrier and resulted in zoonotic disease transmission to humans (Hon, et al. (2008) J. Virol., 82(4): 1819- 1826; Chan, et al. (2013) Trends Microbiol., 21 (10): 544-555; Lu, et al.
  • the SARS-CoV-2 genome has been sequenced and compared with other coronaviruses (CoVs) (Wu, et al. (2020) Nature 579(7798):265-269).
  • CoVs coronaviruses
  • the sequence of the genome confirmed that novel SARS-CoV-2 is a P-CoV, which were originally found in bats and have now adapted to infect humans.
  • CoVs are RNA viruses with positive-sense single stranded RNA (+ssRNA) as their genetic material and SARS-CoV-2 shares around 89% sequence similarity with other SARS-CoVs (Wu, et al. (2020) Nature 579(7798):265-269; U1 Qamar, et al. (2020) J. Pharm.
  • SARS-CoV-2 has similar genetic organization with other SARS-CoVs with a 5'-untranslated region followed by 16 non-structural proteins (open reading frame; ORF la and ORF lb complex) also called as replicase complex, and the structural proteins such as spike (S), envelop (E), membrane (M), and nucleocaspid (N) protein along with other accessory proteins present towards the 3' end (Zhu, et al. (2020) N. Engl. J. Med., 382(8): 727-733).
  • ORF la and ORF lb complex open reading frame
  • structural proteins such as spike (S), envelop (E), membrane (M), and nucleocaspid (N) protein along with other accessory proteins present towards the 3' end
  • the infection with SARS-CoV-2 virus begins with the binding of the S protein of the virus to its receptor - angiotensin converting enzyme 2 (ACE2; GenBank Gene ID: 59272) - on host cells. The binding is then followed by the fusion of the viral envelop with host cell membrane and the release of the viral genome into the cytoplasm (Astuti, et al. (2020) Diabetes Metabol. Syndrome 14(4) :407-412).
  • the viral genome (+ssRNA) hijacks the host ribosomes and gets translated into an ⁇ 800KDa large polypeptide (PP) chain.
  • the SARS- CoV-2 proteases then process the PP into mature viral proteins required for new virion formation.
  • the newly generated PP chain is proteolytically cleaved by the two proteases papain like protease (PLpro) and 3-chyomotrypsin like protease (3CLpro; also known as the main protease-Mpro), encoded by the viral genome, to generate several non-structural proteins (NSPs) required for the viral replication.
  • NSPs non-structural proteins
  • PLpro and 3CLpro cleaves the PP chain into 16 NSPs (Muramatsu, et al. (2016) Proc. Natl. Acad. Sci., 113(46): 12997-13002; Harcourt, et al. (2004) J. Virol., 78(24): 13600-12).
  • NSPs are generated by the 3CLpro, making this protease one of the major targets for developing anti- SARS-CoV drugs (Needle, et al. (2015) Acta Crystallogr D Biol. Crystallogr., 71(Pt 5): 1102- 1111; Anand, et al. (2003) Science 300(5626):1763-1767; Kim, et al. (1995) Virology 208(1): 1-8; Ghosh, et al. (2005) J. Med. Chem., 48(22):6767-71; Macchiagodena, et al. (2020) Chem. Phys.
  • coronavirus 3CLpro has a high degree of sequence homology, making it an attractive drug target for a broad-spectrum inhibitor (Berry, et al. (2015) Viruses 7(12):6642-60).
  • the PLpro cleaves the newly generated PP chain proteolytically to generate 3 NSPs required for the viral replication (Muramatsu, et al. (2016) Proc. Natl. Acad. Sci., 113(46): 12997-13002; Harcourt, et al. (2004) J. Virol., 78(24): 13600-12).
  • SARS-CoV-2 PLpro exhibits deubiquitination (DUB) activity (Mahmoudvand, et al. (2021) Scand. J. Immunol., 2021 :el3044; Lindner, et al. (2007) Arch. Biochem. Biophys., 466(1): 8-14).
  • Ubiquitination a process of attachment of ubiquitin (UB) and ubiquitin like proteins (UBL) to the cellular proteins that needs to be degraded by the host proteasomal complex in cytosol, is an essential process required to maintain the host protein turn over. Ubiquitination also plays an important role in degrading foreign proteins such as viral proteins upon infection to prevent viral propagation (Kikkert, M. (2020) J. Innate Immun., 12(l):4-20). Thus, the deubiquitination activity of SARS-CoV-2 PLpro leads to the disruption of host’s anti-viral immune response.
  • IFN-a/p Type-I interferon
  • ISG-15 interferon-sensitive gene-15
  • JAK, STAT, and IRF-3 signalling molecules
  • ISGylation to mediate the Type-I IFN induced anti-viral function
  • SARS-CoV-2 PLpro mediates de-ISGylation of ISG-15 to the host signalling molecules that leads to the inhibition of the host anti-viral innate immune response (McClain, et al. (2020) Signal Transduct. Target Ther., 5(1):223; Shin, et al. (2020) Nature 587(7835):657-662; Chen, et al. (2014) Protein Cell 5(5):369-81 ; Fung, ET AL. (2019) Annu. Rev. Microbiol., 73:529-557). Therefore, the DUB activity of SARS-CoV-2 dysregulates the primary interferon mediated anti-viral response, which is the hallmark of COVID-19 (Yang, et al.
  • RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2 is a multimeric protein, composed of NSP7, NSP8 and NSP12.
  • RdRp is also called a replicase complex and has over 96% similarity compared to SARS-CoV-1 (Gao, et al. (2020) Science 368(6492):779-782; Arya, et al. (2021) J. Mol. Biol., 433(2): 166725).
  • RdRp enzymatic activity is mainly mediated by NSP12.
  • RpRp incorporates the incoming nucleotide tri-phosphates (NTPs) into the growing nascent RNA chain whereas the NSP7-NSP8 complex performs primase activity to facilitate entry of incoming NTPs and thereby increasing the affinity of RdRp towards its substrates such as NTPs (Arya, et al.
  • nucleoside analogues may result in the development of drug resistances. It has been shown that the 3’-5’ exonuclease activity of NSP14 of SAR-CoVs may excise the nucleoside analogues leading to delayed termination of growing viral RNA genome (Gordon et al. (2020) J. Biol. Chem., 295(20):6785-6797; Agostini, et al. (2016) mBio 9(2):e00221-18). This warrants the development of more potent and non-nucleoside analogues that specifically inhibit the enzymatic activity SARS-CoV-2 RdRp enzyme.
  • FCoVs feline coronaviruses
  • FCoVs feline coronaviruses
  • 3CLpro inhibitors may have potential as therapeutic agents against not only FCoVs but also against other viruses like feline caliciviruses that are important in domestic and wild cats (Kim at al. (2015) J Virol., 89(9): 4942-4950); (Pederson et al. (2016) J Feline Med Surg., 20(4): 378-392).
  • GC376, the compound used as positive control used in the current invention was effective in treating cats with certain presentations of feline infectious peritonitis (Pederson et al. (2016) J Feline Med Surg., 20(4): 378-392) indicating a use of the compounds described in this invention in veterinary medicine.
  • caffeic acid alone is unable to inhibit 3CLpro, PLpro and/or RdRp
  • caffeic acid derivatives of the instant invention have shown efficacy.
  • some of the derivatives exhibited potent inhibition towards PLpro and RdRp, and less potency towards 3CLpro.
  • Bel -2 inhibitors have been shown herein to exhibit inhibitory effects towards 3CLpro enzyme.
  • the molecules of the instant invention are highly specific therapeutically viable drugs for the inhibition of SARS-CoV-2 replication as well as in preserving anti-viral immune responses, either alone or in combination with other drugs specific for other SARS- CoV-2 viral targets.
  • DMSO Molecular biology grade DMSO was from Sigma Aldrich (St. Louis, MO), sterile PBS, penicillin/streptomycin (Pen/Strep) and PrestoBlueTM Cell Viability Reagent were from ThermoFisher Scientific (Waltham, MA).
  • Fetal bovine serum (FBS) from Gemini Bio Products (Sacramento, CA).
  • Recombinant full length untagged 3CLpro, PLpro with His-Tag, assay buffers, inhibitors, fluorescently labelled substrates, Papain-like Protease (SARS-CoV-2), and deubiquitinase assay kits were from BPS Biosciences (San Diego, CA).
  • Bcl-2 inhibitors such as A-1331852, A-l 155463, ABT-199, ABT-263, ABT-333, ABT-737, ABT-737, CAY- 10748, Gambogic acid, HA14-1, Obatoclax, Sabutoclax, TW-37, WEHI-539 were from Sigma Aldrich.
  • the reaction vessel was prepared by purging a 3 -necked round bottom flask of air using an inert gas such as Nitrogen.
  • an inert gas such as Nitrogen.
  • 1.0 gram of amine group containing compound such as 9-amino minocycline, 2 amino 6-nitro benzothiazole, or amino acid was dissolved in DMF under nitrogen followed by the addition of 1.5meq of triethylamine to the reaction mixture. After 15 minutes, 1.5meq of l-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), 4- dimethylaminopyridine (DMAP), hydroxybenzotriazole (HOBt), and 1.0 eq of caffeic acid was dissolved in dimethylformamide (DMF).
  • EDC l-ethyl-3-(3-dimethylaminopropyl)carbodiimide
  • DMAP 4- dimethylaminopyridine
  • HOBt hydroxybenzotriazole
  • the mixture was allowed to react for 48 hours at room temperature. Afterwards, the solvent was removed and an extraction was performed using dichloromethane and water. During the extraction, a methanol soluble solid formed which was collected along with the organic and aqueous layers. If required, the product was purified using silica gel column.
  • Eight millimolar stock solution of the compounds were prepared either in DMSO or PBS.
  • Working solution of 250 pM and 500 pM of each compound was prepared in PBS and used for in vitro enzymatic assay.
  • SARS-CoV-2 specific 3CLpro enzymatic assay was carried out as reported (Mody, et al. (2021) Commun. Biol., 4(1):93) and PLpro proteolytic assay was performed according to the manufacturer protocol. Briefly, 1 ng/pl of 3CLpro and 0.4 ng/pl of PLpro in 30 pl of assay buffer was pre-incubated with the 10 pl of 250 pM compounds for Ihour. Then, the enzymatic reaction was initiated by adding 10 pl of 250 pM fluorescently labeled substrate. Total volume of the assay samples was 50 pl. Deubiquitinase activity of PLpro was estimated as per the manufacturer’s protocol (BPS Biosciences, San Diego).
  • the deubiquitinase assay conditions were similar to PLpro proteolytic assay but the reaction was initiated using PLpro specific ubiquitinated substrate (10 pl of 25 pM to make final concentration 1.25 pM) and incubated for 16-18 hours at room temperature under dark condition. Fluorescent reading was taken at 360/40 excitation and 460/40 nm emission using SynergyTM HT fluorescent plate reader. For dose dependent studies, compounds were screened from 0-100 pM range. 10 pl of 1% DMSO with enzyme and 50 pM of substrate served as positive control. Wells with 50 pM of GC376 and GRL0617 compounds (BPS Biosciences; San Diego, CA) served as specificity controls for 3CLpro and PLpro, respectively. Wells with 1% DMSO, 50 pM of substrate and without enzyme served as blank. All the values were subtracted from blank values to calculate the percent activity of the enzymes.
  • SARS-CoV-2 specific RdRp enzymatic assay was carried out according to the manufacturer protocol with slight modification (ProFoldin Inc, Hudson, MA). Briefly, reaction mixture was prepared by mixing 3.3ml of DNAse/RNAse free water, 400 pl of lOx buffer, 100 pl of 50x template, 100 pl of RdRp and 100 pl of NTPs at 4°C. 10 pl of testing drugs (250 pM) were added to the 96 well plate. Then, 40 pl of ice-cold reaction mixture was added and the reaction was initiated by incubating the 96-well plate at 37°C. The total volume of assay mixture was 50 pl. The incubation was continued for 2 hours.
  • the cytotoxic effect of the Sabatoclaux, 9-Amino-Minocyclin, Minocycline-Caffeic acid, and 4-Nitro-Phenylalaline-Caffeic acid was performed with Calu-3 cells using PrestoBlueTM Cell Viability kit.
  • the assay was carried out as per the manufacturer’s protocol. Briefly, around 20,000 cells were seeded for 24 hours in 96 well plates. Then the cells were refreshed with lOOpl of media (EMEM with 10%FBS and 1% of Pen/Strep) along with 0-25pM of compounds and incubated for 48 hours at 37°C. PrestoBlueTM solution (lOpl) was added and continued the incubation for Ali at 37°C. The absorbance was taken using Bio-Tek Synergy HT fluorescent plate reader.
  • New molecules were developed based on the active site structure of PLpro enzyme using MOE software to identify compounds that could interact with the enzymatic site of PLpro enzyme. Table 1 provides the structures of these compounds.
  • in vitro proteolytic assay using SARS-CoV-2 specific recombinant PLpro enzyme were performed. As shown in Figure 1, 4-nitro-phenylalanine-caffeic acid, glycinecaffeic acid, and tyrosine-caffeic acid derivatives were able to inhibit 30% of PLpro proteolytic activity whereas minocycline-caffeic acid and 9-amino minocycline were able to inhibit more than 90% or completely inhibited the PLpro proteolytic activity at a 50 pM concentration.
  • the parental compounds caffeic acid or minocycline did not significantly inhibit PLpro proteolytic activity.
  • Caffeic acid and minocycline were used as basic scaffolds to make derivatives based on their structural compatibility with the PLpro enzymatic active site.
  • the 2-chloroindole-3 -acrylic acid, 2-methyl indole-aceto-nitrile, 2- methyl-N-indole-ethylamine, tryptophan-caffeic acid, caffeic acid-2, amino-6-nitro benzothiozole and gallic acid-2 amino 6-nitrobeenzothiozole did not significantly inhibit PLpro proteolytic activity.
  • Table 1 Small molecular weight molecules to target the SARS-CoV-2 RdRp, 3CLpro and/or PLpro enzymes. MW: molecular weight.
  • Minocycline-caffeic acid and 9-animo minocycline are superior inhibitors in that they inhibit both proteolytic and DUB activity of the SAR-CoV2 PLpro enzymes. As such, these compounds inhibit the replication of the virus as well as promote IFN-Type-I cytokine mediated anti-viral immune response.
  • both minocycline-caffeic acid and 9-animo minocycline completely inhibited the proteolytic and DUB activity of SARS-CoV2 PLpro enzyme, both of these molecules were further evaluated in dose-dependent studies to calculate the concentration required to inhibit 50% of PLpro enzymatic activity (IC50). As seen in Figure 3, both molecules inhibited 100% of the proteolytic activity of PLpro at 100 pM concentration.
  • the concertation of minocycline-caffeic acid and 9-animo minocycline against the percent activity of PLpro was used to determine the IC50 with non-linear curve fit model as described above.
  • the IC50 value for minocycline-caffeic acid and 9-animo minocycline was found to be 4.52 and 4.15 pM, respectively, for proteolytic activity.
  • the RdRp complex is pivotal during replication and transcription of the SAR-CoV-2 viral genome. Therefore, the ability of the molecules to inhibit the RdRp enzymatic activity was tested. As shown in Figure 5, only 4-nitro-phenylalanine-caffeic acid derivative was able to inhibit up to 80% of RdRp enzymatic activity. These studies indicate that the 4-nitro- phenylalanine-caffeic acid derivative exhibits more selectivity towards SARS-CoV-2 RdRp compared to 3CLpro and PLpro enzymes.
  • Table 2 provides a summary of the tested compounds against 3CLpro, PLpro, and
  • 'able 2 Inhibitory effect of compounds on SARS-CoV-2 enzymes.
  • Table 3 Small molecular weight molecules to target the SARS-CoV-2 3CLpro and PLpro enzymes. MW: molecular weight (daltons).
  • A-1331852 and sabutoclax were subjected to subsequent dose-dependent studies to calculate the concentration required to inhibit 50% of the 3CLpro enzymatic activity (IC50).
  • IC50 concentration required to inhibit 50% of the 3CLpro enzymatic activity
  • A-1331852 inhibited more than 70% of the enzymatic activity at a 50 pM concentration, and 100% of the enzymatic activity at a 100 pM concentration.
  • Sabutoclax was also able to inhibit 100% of the enzymatic activity at thelOO pM concentration ( Figure 7).
  • the percent enzymatic activity versus the log concentration of the inhibitors was used to calculate the IC50 values using non-linear curve fit model as described above.
  • the calculated IC50 values for A-1331852 and sabutoclax were found to be 21.62 and 18.71 pM, respectively. Further, A-1331852 was able inhibit approximately 70% of PLpro proteolytic activity, whereas gambogic acid and sabutoclax exhibited only 50% inhibitory activity (Figure 8). These data indicate that A-1331852 is able to inhibit both 3CLpro and PLpro enzymes, but sabutoclax exhibits more specificity towards the inhibition of 3CLpro ( Figure 6). Taken together, these studies indicate that A-1331852 inhibits the proteolytic activity of both 3CLpro and PLpro whereas sabutoclax is more specific for 3CLpro. Minocycline- caffeic acid and 9-amino minocycline are specific towards PLpro enzyme of SARS-CoV-2.
  • Table 4 provides a summary of the inhibitory properties of Bcl2 inhibitors.
  • Table 4 Inhibitory effect of Bcl2 inhibitors on SARS-CoV-2 enzymes.
  • the SARS-CoV-2 virus is responsible for causing COVID-19, which is now a global threat especially with the emerging variants because of their high infectivity and mortality rate (Davies, et al. (2021) Nature 593(7858):270-274; Challen, et al. (2021) BMJ 372:n579; Majumdar, et al. (2020) Epidemiol Infect., 148:e262; Motayo, et al. (2021) Int. J. Infect. Dis., 103:282-287). Though vaccines have been developed and are still in pursuit, there are no SARS-CoV-2 specific drugs available to stop the spread of this virus.
  • SARS-CoV-2 mainly spreads through respiratory droplets (Meselson, M. (2020) N. Engl. J. Med., 382(21):2063). Therefore, there is an immediate need to identify potential molecules that can inhibit the viral replication.
  • Targeting viral replicative enzymes such as viral proteases are a viable approach to control the viral replication as observed with in the treatment of HIV and Hepatitis-C infections (Lv, et al.
  • an in vitro cellbased viral challenge study was performed using the SARS-CoV-2 Delta variant in the Calu- 3 human lung adenocarcinoma cell line. Briefly, Calu-3 cells were infected with 1.0 multiplicity of infection (MOI) of a Delta SARS-CoV-2 variant. Sabatoclaux, 9-Amino- Minocyclin, Minocycline-Caffeic acid, and 4-Nitro-Phenylalaline-Caffeic acid at 6.25 pM was added to the cells at the time of infection respectively. Viral load was quantified in 48 hour culture supernatant using RT-qPCR with primers targeting the E gene of SARS-CoV-2.
  • MOI multiplicity of infection
  • SARS-CoV-2 3CLpro is the main enzyme required for viral replication and a drug target for SARS-CoV-2 (Zumla, et al. (2016) Nat. Rev. Drug Discov., 15(5):327-347). Recently, Pfizer developed a compound PF-00835231 specific for SAR-CoVl/ SAR-CoV2 3CLpro enzyme that has advanced to clinical trials (Britton et al. (2021) bioRxiv 12: 1-67). However, currently, there are no potential therapeutics that have been developed to inhibit the PLpro enzyme. SARS-CoV-2 PLpro enzyme is a protease required to generate the NSPs essential for viral replication through its protease activity (Lindner, et al. (2005) J.
  • PLpro also exhibits de-ubiquitination in order to prevent the INF-a/p mediated anti-viral activity, thus may be responsible for pro-inflammatory cytokine storm in COVID-19 patients (Mahmoudvand, et al. (2021) Scand. J. Immunol., 2021 :el3044; Sulea, et al. (2005) J. Virol., 79(7):4550-4551; Yuen, et al. (2020) Emerg. Microbes Infect., 9(1): 1418-1428; Morales, et al. (2013) J. Mol. Biol., 425(24):4995-5008).
  • PLpro serves as an excellent drug target, not only to control the viral replication, but also to prevent the cytokine tsunami in COVD-19 patients. It can be advantageous to develop a therapeutic strategy to target both 3CLpro and PLpro to control viral spread and SAR-CoV-2 mediated inflammatory damage to tissues.
  • potent molecules that selectively and specifically inhibit both proteolytic and DUB activity of SARS-CoV2 PLpro enzyme have been provided.
  • a Bcl-2 inhibitor has been identified which specifically inhibits the proteolytic activity of 3CLpro but possess minimal inhibitory activity towards PLpro enzyme.
  • SARS-CoV-2 RdRp plays a pivotal role in viral replication by facilitating viral genome replication required for new virion formation (Ga, et al. (2020) Science 368(6492):779-782; Arya, et al. (2021) J. Mol. Biol., 433(2): 166725).
  • the nucleoside analogue remdesivir inhibits SARS-CoV-2 RdRp enzyme and is approved to treat SARS-CoV-2 infection (Gordon, et al. (2020) J. Biol. Chem., 295(20):6785-6797).

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Abstract

La présente divulgation concerne des composés pour inhiber des protéines de coronavirus, des compositions les comprenant, et un procédé d'utilisation de ceux-ci pour traiter des infections à coronavirus, en particulier des infections à SARS-CoV-2.
PCT/US2023/011690 2022-01-27 2023-01-27 Compositions et procédés d'inhibition du coronavirus 2 du syndrome respiratoire aigu sévère (sras) (sars-cov-2) WO2023147011A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
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WO2004038000A2 (fr) * 2002-10-24 2004-05-06 Paratek Pharmaceuticals, Inc. Procedes d'utilisation de composes tetracycline substituee pour moduler l'arn
US20100173991A1 (en) * 2007-07-20 2010-07-08 Peter Lorenz Method for the synthesis of a-ring aromatized acetyl minocyclines
US20180016225A1 (en) * 2001-07-13 2018-01-18 Paratek Pharmaceuticals, Inc. Tetracycline compounds having target therapeutic activities
US20210403416A1 (en) * 2018-06-13 2021-12-30 Texas Tech University System Novel Modified Tetracyclines for Treatment of Alcohol Use Disorder, Pain and Other Disorders Involving Potential Inflammatory Processes

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Publication number Priority date Publication date Assignee Title
US20180016225A1 (en) * 2001-07-13 2018-01-18 Paratek Pharmaceuticals, Inc. Tetracycline compounds having target therapeutic activities
WO2004038000A2 (fr) * 2002-10-24 2004-05-06 Paratek Pharmaceuticals, Inc. Procedes d'utilisation de composes tetracycline substituee pour moduler l'arn
US20150321997A1 (en) * 2002-10-24 2015-11-12 Paratek Pharmaceuticals, Inc. Methods of using substituted tetracycline compounds to modulate rna
US20100173991A1 (en) * 2007-07-20 2010-07-08 Peter Lorenz Method for the synthesis of a-ring aromatized acetyl minocyclines
US20210403416A1 (en) * 2018-06-13 2021-12-30 Texas Tech University System Novel Modified Tetracyclines for Treatment of Alcohol Use Disorder, Pain and Other Disorders Involving Potential Inflammatory Processes

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Title
DATABASE PUBCHEM COMPOUND ANONYMOUS : "4,7-bis(dimethylamino)-9-fluoro-1,10,11,12a-tetrahydroxy-3,12-dioxo-4a,5,5a,6-tetrahydro-4H-tetracene-2-carboxamide", XP093083479, retrieved from PUBCHEM *

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