ASK1 inhibitors are potential pan-antiviral drugs, which dampen replication of diverse viruses including SARS-CoV2

Wael L Demian; Rajesh Abraham Jacob; Olga Cormier; Aisha Nazli; Matthew Melki; Akarin Asavajaru; Kaushal Baid; Ali Zhang; Matthew S Miller; Charu Kaushic; Arinjay Banerjee; Karen Mossman

doi:10.1016/j.antiviral.2023.105736

ASK1 inhibitors are potential pan-antiviral drugs, which dampen replication of diverse viruses including SARS-CoV2

Antiviral Res. 2023 Dec:220:105736. doi: 10.1016/j.antiviral.2023.105736. Epub 2023 Oct 18.

Authors

Affiliations

¹ Department of Medicine, McMaster University, Hamilton, ON, Canada; Michael G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, ON, Canada; McMaster Immunology Research Centre, McMaster University, Hamilton, ON, Canada.
² Michael G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, ON, Canada; McMaster Immunology Research Centre, McMaster University, Hamilton, ON, Canada; Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada.
³ Vaccine and Infectious Disease Organization, University of Saskatchewan, Saskatoon, SK, S7N 5E3, Canada.
⁴ Vaccine and Infectious Disease Organization, University of Saskatchewan, Saskatoon, SK, S7N 5E3, Canada; Department of Veterinary Microbiology, University of Saskatchewan, Saskatoon, SK, S7N 5B4, Canada.
⁵ Department of Medicine, McMaster University, Hamilton, ON, Canada; Michael G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, ON, Canada; McMaster Immunology Research Centre, McMaster University, Hamilton, ON, Canada; Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada. Electronic address: mossk@mcmaster.ca.

PMID: 37863359
DOI: 10.1016/j.antiviral.2023.105736

Abstract

Apoptosis signal-regulating kinase 1 (ASK1)/MAP3K5 is a stress response kinase that is activated by various stimuli. It is known as an upstream activator of p38- Mitogen-activated protein kinase (p38MAPK) and c-Jun N-terminal kinase (JNK) that are reactive oxygen species (ROS)-induced kinases. Accumulating evidence show that ROS accumulate in virus-infected cells. Here, we investigated the relationship between viruses and ASK1/p38MAPK or ASK1/JNK pathways. Our findings suggest that virus infection activates ASK1 related pathways. In parallel, ASK1 inhibition led to a remarkable reduction in the replication of a broad range of viruses including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), vaccinia virus (VV), vesicular stomatitis virus (VSV), Herpes Simplex Virus (HSV), and Human Immunodeficiency virus (HIV) in different human cell lines. Our work demonstrates the potential therapeutic use of Selonsertib, an ASK1 inhibitor, as a pan-antiviral drug in humans. Surprisingly, we observed differential effects of Selonsertib in in vitro and in vivo hamster models, suggesting caution in using rodent models to predict clinical and therapeutic outcomes in humans.

Keywords: ASK1; Antiviral; Herpes simplex virus; SARS-CoV-2; Selonsertib; Vesicular stomatitis virus.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antiviral Agents / pharmacology
Apoptosis
COVID-19*
Humans
JNK Mitogen-Activated Protein Kinases / metabolism
MAP Kinase Kinase Kinase 5 / metabolism
MAP Kinase Kinase Kinase 5 / pharmacology
RNA, Viral
Reactive Oxygen Species
SARS-CoV-2 / metabolism
Signal Transduction*
p38 Mitogen-Activated Protein Kinases / metabolism

Substances

selonsertib
RNA, Viral
MAP Kinase Kinase Kinase 5
Reactive Oxygen Species
Antiviral Agents
p38 Mitogen-Activated Protein Kinases
JNK Mitogen-Activated Protein Kinases