The pursuit of broad-spectrum antivirals: leveraging structural insights into viral proteases
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Authors
Greene-Cramer, Rebecca
Issue Date
2025-05
Type
Electronic thesis
Thesis
Thesis
Language
en_US
Keywords
Chemistry
Alternative Title
Abstract
Emerging viral pathogens, such as SARS-CoV-2, the causative agent of COVID-19, present a global health threat, necessitating preparedness to mitigate future outbreaks. While public health strategies help curb transmission, there is a pressing need for effective broad-spectrum antiviral therapies deployable during the early stages of future outbreaks. Structural bioinformatic analyses reveal significant similarities between the substrate-binding sites of SARS-CoV-2 3C-like protease (3CLpro) and other viral proteases within the PA Clan enzyme superfamily, including key antiviral drug development targets like MERS 3CL protease, Dengue Virus NS2B-NS3 protease, and Hepatitis C Virus NS2/3A protease. Guided by this structural similarity, prior studies from our laboratory have shown that several HCV protease inhibitors can bind and inhibit SARS-CoV-2 3CLpro. In this study, we present results on investigations of cross-inhibition among structurally similar PA Clan proteases, including initial findings from a comprehensive all vs. all screening. We evaluated the cross-inhibitory activities of 18 commercially available inhibitors, together with molecules obtained from collaborators, targeting specific PA Clan proteases against the proteases of SARS-CoV-1, SARS-CoV-2, MERS, Polio, Dengue, West Nile and Zika viruses. Proteases from these viruses were cloned, expressed, and purified, and fluorescence- and NMR-based enzyme assays were developed. Using this approach, we have successfully identified several novel viral protease inhibitors of MERS, Polio, Dengue, West Nile and Zika virus proteases. Our studies provide novel directions for antiviral drug development targeting a wide range of pathogenic viruses with pandemic potential.
Description
May2025
School of Science
School of Science
Full Citation
Publisher
Rensselaer Polytechnic Institute, Troy, NY