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Updated: Jun 8, 2025
High-throughput Screening for Broad-spectrum Chemical Inhibitors of RNA Viruses
Published on: May 5, 2014
Targeting protein homeostasis with small molecules as a strategy for the development of pan-coronavirus antiviral
Yu-Qian Mao1, Shahrzad Jahanshahi1,2, Ramy Malty1,3
1Department of Biochemistry, University of Toronto, Toronto, ON, Canada.
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.
Insights
Researchers developed broad-spectrum antiviral therapies targeting host cell mechanisms to combat evolving coronaviruses like SARS-CoV-2. Three compounds showed efficacy against multiple strains, including delta and omicron variants, inhibiting viral replication in vitro and in organoids.
Area of Science:
- Virology
- Drug Discovery
- Molecular Biology
Background:
- The COVID-19 pandemic presents ongoing challenges due to SARS-CoV-2 evolution and new variants.
- Viral resistance necessitates the development of novel, broad-spectrum antiviral therapies.
- Targeting host cell mechanisms offers a strategy to overcome viral resistance.
Purpose of the Study:
- To develop broad-spectrum pan-coronavirus antiviral therapies.
- To identify compounds targeting host protein quality control mechanisms essential for viral replication.
- To evaluate the efficacy of identified compounds against SARS-CoV-2 and its variants.
Main Methods:
- Screening of an in-house compound library targeting cellular proteostasis.
- In vitro testing of candidate compounds against multiple coronaviruses, including SARS-CoV-2.
- Evaluation of antiviral efficacy in lung organoids and against specific SARS-CoV-2 strains (delta, omicron).
- Development of a BSL2-level cell-integrated SARS-CoV-2 replicon for high-throughput screening.
Main Results:
- Three compounds (cordycepin, benzothiozole analog, acyldepsipeptide analog) were identified.
- Compounds demonstrated dose-dependent inhibition of viral replication in vitro and in lung organoids.
- Efficacy was observed against SARS-CoV-2, including delta and omicron variants.
Conclusions:
- Targeting host proteostasis provides a promising strategy for broad-spectrum antiviral drug development.
- The identified compounds represent potential candidates for pan-coronavirus therapies.
- The developed SARS-CoV-2 replicon is a valuable tool for future antiviral research.
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