Protective agents for endothelial dysfunction

Abstract

Methods for treating, improving, and / or preventing endothelial dysfunction caused by SARS-CoV-2 in subjects where such treatment is necessary are described herein. Methods for treating and / or improving coronavirus infection are also described herein. Both methods include administering an effective amount of a peptide capable of inhibiting the phospholipase A2 (PLA2) activity of peroxiredoxin 6 (Prdx6) to a subject.

Claims

1. A method of treating, improving, and / or preventing endothelial dysfunction caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in a subject that requires it, wherein X is SEQ ID NO: 4 1 X 2 X 3 X 4 X 5 LX 6 X 7 X 8 X 9 comprising administering to the subject an effective amount of a polypeptide consisting of HQIL Here, X 1 It may or may not exist, and if it exists, it is E; X 2 It may or may not exist, and if it exists, it is L; X 3 It may or may not exist, and if it exists, it is Q; X 4 It may or may not exist, and if it exists, it is A or T; X 5 is either T or E; X 6 is either H or Y; X 7 is either D or E; X 8 is F or I; X 9 is R or K. method.

2. The polypeptide described above, The method according to claim 1, selected from the group consisting of the following.

3. The method according to claim 1 or claim 2, wherein the polypeptide is formulated in liposomes.

4. The method according to any one of claims 1 to 3, wherein the polypeptide is formulated in a pharmaceutical composition containing a pharmaceutically acceptable carrier.

5. The method according to any one of claims 1 to 4, wherein the step of administering the polypeptide to the subject includes aerosol inhalation, intratracheal injection, intravenous injection, or any combination thereof.

6. The method according to any one of claims 1 to 5, wherein the endothelial dysfunction includes endothelial activation and / or an endothelial inflammatory phenotype.

7. The method according to any one of claims 1 to 6, wherein the endothelial dysfunction occurs in at least the pulmonary endothelial tissue of the subject.

8. The method according to claim 7, wherein the administration results in the prevention of reactive oxygen species (ROS) production from cells of pulmonary endothelial tissue, or a reduction in ROS production compared to a reference level of ROS production before administration of the polypeptide.

9. The method according to claim 8, wherein the reduction in ROS production is at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 100%, or more, compared to a reference level of ROS production before administration of the polypeptide.

10. below: (a) The administration results in the prevention of intercellular adhesion molecule 1 (ICAM-1) expression from cells of pulmonary endothelial tissue, or a reduction in ICAM-1 expression compared to a reference level of ICAM-1 expression before administration of the polypeptide. (b) The administration results in the prevention of NLR family pyrine domain-containing (NLRP3) expression from cells of pulmonary endothelial tissue, or a reduction in NLRP3 expression compared to a reference level of NLRP3 expression before administration of the polypeptide, or (c) The administration results in the prevention of caspase-1 levels from cells in pulmonary endothelial tissue, or a reduction in caspase-1 levels compared to the reference level of caspase-1 expression before administration of the polypeptide. The method according to claim 7, wherein at least one of the following is met.

11. below: (a) The reduction in ICAM-1 expression is at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 100%, or more, compared to the reference level of ICAM-1 expression before administration of the polypeptide. (b) The reduction in NLRP3 expression is at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 100%, or more, compared to the reference level of NLRP3 expression before administration of the polypeptide. (c) The reduction in caspase 1 level is at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 100%, or more, compared to the reference level of caspase 1 level before administration of the polypeptide. The method according to claim 10, wherein at least one of the following is met.

12. The method according to any one of claims 1 to 11, wherein the subject is a mammal.

13. The method according to claim 12, wherein the mammal is selected from humans, non-human primates, cattle, pigs, horses, sheep, deer, rabbits, otters, minks, voles, ferrets, bats, raccoons, cats, dogs, hamsters, rats, and mice.

14. The method according to claim 13, wherein the subject is a human being.

15. The method according to any one of claims 1 to 14, wherein the subject is active SARS-CoV-2 infection, coronavirus disease 2019 (COVID-19), and / or post-acute sequelae SARS-CoV-2 infection (PASC).

16. The method according to any one of claims 1 to 15, wherein the SARS-CoV-2 is a SARS-CoV-2 variant.

17. The method according to claim 16, wherein the SARS-CoV-2 variant is selected from alpha (B.1.1.7 and Q lineage), beta (B.1.351 and progeny lineage), gamma (P.1 and progeny lineage), delta (B.1.617.2 and AY lineage), epsilon (B.1.427 and B.1.429), zeta (P.2), etha (B.1.525), iota (B.1.526), ​​kappa (B.1.617.1), 1.617.3, mu (B.1.621 and B.1.621.1), and omicron (B.1.1.529 and BA lineage (BA.1, BA.1.1, and BA.2)).

18. A method for treating or improving coronavirus infection in a person who needs it, and whose SEQ ID NO: 4 X 1 X 2 X 3 X 4 X 5 LX 6 X 7 X 8 X 9 The process includes administering an effective amount of a polypeptide consisting of HQIL to the subject, Here, X 1 It may or may not exist, and if it exists, it is E; X 2 It may or may not exist, and if it exists, it is L; X 3 It may or may not exist, and if it exists, it is Q; X 4 It may or may not exist, and if it exists, it is A or T; X 5 is either T or E; X 6 is either H or Y; X 7 is either D or E; X 8 is F or I; X 9 is R or K. method.

19. The polypeptide described above, The method according to claim 18, selected from the group consisting of the following.

20. The method according to claim 18 or claim 19, wherein the polypeptide is formulated in liposomes.

21. The method according to any one of claims 18 to 20, wherein the polypeptide is formulated in a pharmaceutical composition comprising a pharmaceutically acceptable carrier.

22. The method according to any one of claims 18 to 21, wherein the step of administering the polypeptide to the subject includes aerosol inhalation, intratracheal injection, intravenous injection, or any combination thereof.

23. The method according to any one of claims 18 to 22, wherein the coronavirus infection causes endothelial dysfunction in the subject.

24. The method according to claim 23, wherein the endothelial dysfunction includes endothelial activation and / or endothelial inflammatory phenotypes.

25. The method according to any one of claims 23 to 24, wherein the endothelial dysfunction occurs in at least the pulmonary endothelial tissue of the subject.

26. The method according to claim 25, wherein the administration results in the prevention of reactive oxygen species (ROS) production from cells of pulmonary endothelial tissue, or a reduction in ROS production compared to a reference level of ROS production before administration of the polypeptide.

27. The method according to claim 26, wherein the reduction in ROS production is at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 100%, or more, compared to a reference level of ROS production before administration of the polypeptide.

28. below: (a) The administration results in the prevention of intercellular adhesion molecule 1 (ICAM-1) expression from cells of pulmonary endothelial tissue, or a reduction in ICAM-1 expression compared to a reference level of ICAM-1 expression before administration of the polypeptide. (b) The administration results in the prevention of NLR family pyrine domain-containing (NLRP3) expression from cells of pulmonary endothelial tissue, or a reduction in NLRP3 expression compared to a reference level of NLRP3 expression before administration of the polypeptide, or Administer the aforementioned polypeptide, or (c) The administration results in the prevention of caspase 1 activation from cells in pulmonary endothelial tissue, or a reduction in caspase 1 levels compared to the reference level of caspase 1 levels before administration of the polypeptide. The method according to claim 25, wherein at least one of the following is met.

29. below: (a) The reduction in ICAM-1 expression is at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 100%, or more, compared to the reference level of ICAM-1 expression before administration of the polypeptide. (b) The reduction in NLRP3 expression is at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 100%, or more, compared to the reference level of NLRP3 expression before administration of the polypeptide. Compared to the reference level of NLRP3 expression before administration of the polypeptide, there is a reduction of %, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 100%, or more. (c) The reduction in caspase 1 level is at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 100%, or more, compared to the reference level of caspase 1 level before administration of the polypeptide. The method according to claim 28, wherein at least one of the following is met.

30. The method according to any one of claims 18 to 29, wherein the subject is a mammal.

31. The method according to claim 30, wherein the mammal is selected from humans, non-human primates, cattle, pigs, horses, sheep, deer, rabbits, otters, minks, voles, ferrets, bats, raccoons, cats, dogs, hamsters, rats, and mice.

32. The method according to claim 31, wherein the subject is a human being.

33. The method according to any one of claims 18 to 32, wherein the coronavirus comprises at least one selected from the group consisting of SARS-CoV, MERS-CoV, SARS-CoV2, HCoV-OC43, HCoV-HKU1, HCoV-229E, and HCoV-NL63.

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