Targeting protein homeostasis with small molecules as a strategy for the development of pan-coronavirus antiviral therapies

Targeting protein homeostasis with small molecules as a strategy for the development of pan-coronavirus antiviral therapies

Abstract 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 develo...

Full description

Saved in:
Bibliographic Details
Main Authors: Yu-Qian Mao, Shahrzad Jahanshahi, Ramy Malty, David A. J. Van Ommen, Yimei Wan, Trevor M. Morey, Stephanie H. W. Chuang, Veronika Pavlova, Choudhary Ahmed, Subha Dahal, Funing Lin, Maria Mangos, Jocelyn Nurtanto, Yuetong Song, Terek Been, Natasha Christie-Holmes, Scott D. Gray-Owen, Mohan Babu, Amy P. Wong, Robert A. Batey, Liliana Attisano, Alan Cochrane, Walid A. Houry
Format: Article
Language:English
Published: Nature Portfolio 2024-11-01
Series:Communications Biology
Online Access:https://doi.org/10.1038/s42003-024-07143-z
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Abstract 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.
ISSN:2399-3642

Similar Items