Compositions and methods for treating viruses

Patent metadata

Field	Value
Publication number	US-2023158049-A1
Application number	US-202117917407-A
Country	US
Kind code	A1
Filing date	Apr 6, 2021
Priority date	Apr 6, 2020
Publication date	May 25, 2023
Grant date	—

Abstract

Disclosed are compositions and methods that can be used for the prevention, mitigation, and/or prophylactic treatment of a viral infection, such but not limited to a coronavirus infection, such as but not limited to a COVID-19 infection. In some embodiments, a chemically modified tetracycline (CMT) derivative for the prevention, mitigation and/or prophylactic treatment of a viral infection is provided. In some embodiments, the CMT derivative lacks anti-microbial activity; comprises a phenol ring; and/or comprises a chemical structure sufficient to chelate and/or bind a divalent cation. In some embodiments, the divalent cation comprises Zn 2+ . In some embodiments, the viral infection is a coronavirus infection. In some embodiments, the viral infection is a COVID-19 infection.

First claim

What is claimed is:

1 . A method of preventing, mitigating and/or prophylactically treating a viral infection in a subject, the method comprising administering to a subject in need thereof a dose of a chemically modified tetracycline (CMT) derivative, wherein the CMT derivative comprises a phenol ring, and comprises a chemical structure sufficient to chelate and/or bind a divalent cation, wherein the dose of the CMT derivative is below a minimum inhibitory concentration for antimicrobial activity.

2 . The method of claim 1 , wherein the viral infection is a coronavirus infection, optionally a COVID-19 infection.

3 . The method of claim 1 or claim 2 , wherein the CMT derivative lacks antimicrobial activity, optionally wherein the CMT derivative lacks antimicrobial activity due to deletion of a C4 dimethylamino.

4 . The method of claim 1 or claim 2 , wherein the phenol ring comprises a diethylamino group to enhance scavenging of reactive oxygen species.

5 . The method of claim 1 or claim 2 , wherein the chemical structure comprises the following structure:

6 . The method of claim 1 or claim 2 , wherein the CMT derivative is doxycycline.

7 . The method of any of the above claims, wherein the CMT derivative is given at a dose of about 40 mg per day or less, optionally less than about 50 mg per 30 day, less than about 60 mg per day, less than about 70 mg per day, less than about 80 mg per day, less than about 90 mg per day, or less than about 100 mg per day.

8 . The method of any of the above claims, wherein the CMT derivative is configured to inhibit metalloproteinases (MMPs), optionally MMP-9, optionally any MMP implicated in respiratory distress syndrome (ARDS).

9 . The method of any of the above claims, wherein the CMT derivative is configured to inhibit IL6 and other cytokine production.

10 . The method of any of the above claims, wherein the CMT derivative is configured to inhibit Papain-like protease (PLpro), optionally wherein inhibition of PLpro prevents proteolytic cleavage of a replicase polyprotein needed for viral replication, optionally wherein the replicase polyprotein is non-structural proteins 1, 2 and/or 3 (Nsp1, Nsp2 and/or Nsp3).

11 . The method of any of the above claims, wherein the CMT derivative is configured to inhibit and/or bind 3C-like main protease (3CLpro) and/or Nsp5, optionally wherein inhibition and/or binding of 3CLpro and/or Nsp5 prevents viral replication.

12 . The method of any of the above claims, wherein the CMT derivative is configured to bind a divalent cation and transport the divalent cation intracellularly, optionally wherein transporting divalent cations intracellularly increases an intracellular concentration of the cation to thereby inhibit viral replication.

13 . The method of any of the above claims, wherein the subject is a human subject, optionally wherein the human subject is suffering from a coronavirus infection.

14 . The method of any of the above claims, further comprising administering to the subject a dose of a divalent cation, optionally Zn 2+ , optionally wherein the divalent cation or Zn 2+ is administered at a dosage of about 4 mg/day to about 50 mg/day.

15 . A composition for administration to a subject, the composition comprising a chemically modified tetracycline (CMT) derivative, wherein the CMT derivative optionally lacks anti-microbial activity, comprises a phenol ring, and comprises a chemical structure sufficient to chelate and/or bind a divalent cation, optionally Zn 2+ , and wherein the CMT derivative is included in the composition at a concentration sufficient to provide a dose of about 40 mg per day or less, optionally less than about 50 mg per day, less than about 60 mg per day, less than about 70 mg per day, less than about 80 mg per day, less than about 90 mg per day, or less than about 100 mg per day when administered to a subject.

16 . The composition of claim 15 , further comprising a source of a divalent cation, optionally a source of Zn 2+ , optionally wherein the divalent cation or Zn 2+ is included in the composition at a concentration sufficient to provide a dose of about 4 mg/day to about 40 mg/day when administered to a subject.

17 . The composition of claim 15 or claim 16 , wherein the composition is configured to prevent, mitigate and/or prophylactically treat a viral infection, optionally a coronavirus infection, optionally a COVID-19 infection, when administered to a subject.

18 . The composition of any of claims 15 - 17 , wherein the CMT derivative lacks antimicrobial activity due to deletion of a C4 dimethylamino.

19 . The composition of any of claims 15 - 18 , wherein the CMT derivative lacks antimicrobial activity due to dosing below a minimum inhibitory concentration.

20 . The composition of any of claims 15 - 17 and 19 , wherein the CMT derivative is doxycycline.

21 . The composition of any of claims 15 - 20 , further comprising an excipient or a pharmaceutically acceptable carrier.

22 . The composition of any of claims 15 - 21 , wherein the CMT derivative is configured to inhibit metalloproteinases (MMPs), optionally MMP-9, optionally any MMP implicated in respiratory distress syndrome (ARDS).

23 . The composition of any of claims 15 - 22 , wherein the CMT derivative is configured to inhibit IL6 and other cytokine production.

24 . The composition of any of claims 15 - 23 , wherein the CMT derivative is configured to inhibit Papain-like protease (PLpro), optionally wherein inhibition of PLpro prevents proteolytic cleavage of a replicase polyprotein needed for viral replication, optionally wherein the replicase polyprotein is non-structural proteins 1, 2 and/or 3 (Nsp1, Nsp2 and/or Nsp3).

25 . The composition of any of claims 15 - 24 , wherein the CMT derivative is configured to inhibit and/or bind 3C-like main protease (3CLpro) and/or Nsp5, optionally wherein inhibition and/or binding of 3CLpro and/or Nsp5 prevents viral replication.

26 . The composition of any of claims 15 - 25 , wherein the CMT derivative is configured to bind a divalent cation and transport the divalent cation intracellularly, optionally wherein transporting divalent cations intracellularly increases an intracellular concentration of the cation to thereby inhibit viral replication.

27 . A chemically modified tetracycline (CMT) derivative for the prevention, mitigation and/or prophylactic treatment of a viral infection, wherein the CMT derivative comprises a phenol ring; and comprises a chemical structure sufficient to chelate and/or bind a divalent cation.

28 . The CMT derivative of claim 27 , wherein the CMT derivative can have antimicrobial activity due to a dosing at or above a minimum inhibitory concentration.

29 . The CMT derivative of claim 27 or claim 28 , wherein the viral infection is a coronavirus infection, optionally a COVID-19 infection.

30 . The CMT derivative of claim 27 or claim 29 , wherein the CMT derivative lacks anti-microbial activity.

31 . The CMT derivative of claim 30 , wherein the CMT derivative lacks antimicrobial activity due to deletion of a C4 dimethylamino or wherein the CMT derivative lacks antimicrobial activity due to dosing below a minimum inhibitory co

Assignees

• Reichel Elias
• Univ Virginia Patent Foundation

Inventors

• Yates Paul Andrew
• Reichel Elias
• Leone Ashton

Classifications

• A61P31/12 Primary

  Antivirals · CPC title

• A61K33/30

  Zinc; Compounds thereof · CPC title

• A61K31/65 Primary

  Tetracyclines · CPC title

• A61P31/14

  for RNA viruses · CPC title