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

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.

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Publication Details

Journal
Communications Biology
Published
2024-11-07
DOI
https://doi.org/10.1038/s42003-024-07143-z
Citations
2
Primary Topic
SARS-CoV-2 and COVID-19 Research
Type
article
Field-Weighted Citation Impact
0.78

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article

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

Terek Been, Ramy Malty, Stephanie H. W. Chuang, Subha Dahal et al.
2 citations
Communications Biology
SARS-CoV-2 and COVID-19 Research
0.78
article

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

Terek Been, Ramy Malty, Stephanie H. W. Chuang, Subha Dahal, Young Eun Song, Yimei Wan, Alan Cochrane, Scott D. Gray‐Owen, Trevor M. Morey, Maria Mangos, Вера Ивановна Павлова, Shahrzad Jahanshahi, Funing Lin, Mohan Babu, Amy P. Wong, Natasha Christie-Holmes, Walid A. Houry, Robert A. Batey, Liliana Attisano, Yu-Qian Mao, David A. J. Van Ommen, C. M. Sabbir Ahmed, Jocelyn Nurtanto
article en
2 citations

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.

Communications BiologyVol. 7(1)
University of Toronto (CA), University of Regina (CA), Hospital for Sick Children (CA)
Sunnybrook Research Institute, University of Toronto, Mitacs, Canada First Research Excellence Fund, Canadian Institutes of Health Research, Natural Sciences and Engineering Research Council of Canada
Openalex Percentile: Top 27%
SARS-CoV-2 and COVID-19 Research
0.78
DOIOpen Access PDFOpenAlex
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