Targeting protein homeostasis with small molecules as a strategy for the development of pan-coronavirus antiviral therapies
Summary
The COVID-19 pandemic has created a global health crisis, with challenges arising from the ongoing evolution of the SARS-CoV-2 virus, the emergence of new strains, and the long-term effects of COVID-19. Aiming to overcome the development of viral resistance, our study here focused on developing broad-spectrum pan-coronavirus antiviral therapies by targeting host protein quality control mechanisms essential for viral replication. Screening an in-house compound library led to the discovery of three candidate compounds targeting cellular proteostasis. The three compounds are (1) the nucleotide analog cordycepin, (2) a benzothiozole analog, and (3) an acyldepsipeptide analog initially developed as part of a campaign to target the mitochondrial ClpP protease. These compounds demonstrated dose-dependent efficacy against multiple coronaviruses, including SARS-CoV-2, effectively inhibiting viral replication in vitro as well as in lung organoids. Notably, the compounds also showed efficacy against SARS-CoV-2 delta and omicron strains. As part of this work, we developed a BSL2-level cell-integrated SARS-CoV-2 replicon, which could serve as a valuable tool for high-throughput screening and studying intracellular viral replication. Our study should aid in the advancement of antiviral drug development efforts. © 2024. The Author(s).
| Authors | Mao YQ, Jahanshahi S, Malty R, Van Ommen DAJ, Wan Y, Morey TM, Chuang SHW, Pavlova V, Ahmed C, Dahal S, Lin F, Mangos M, Nurtanto J, Song Y, Been T, Christie-Holmes N, Gray-Owen SD, Babu M, Wong AP, Batey RA, Attisano L, Cochrane A, Houry WA |
|---|---|
| Journal | Communications biology |
| Publication Date | 2024 Nov 7;7(1):1460 |
| PubMed | 39511285 |
| PubMed Central | PMC11543989 |
| DOI | 10.1038/s42003-024-07143-z |