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Updated: Jul 19, 2025
Chemoselective Modification of Viral Surfaces via Bioorthogonal Click Chemistry
Published on: August 19, 2012
Alkyne as a Latent Warhead to Covalently Target SARS-CoV-2 Main Protease
Chau Ngo1, William Fried2, Saba Aliyari3
1Department of Chemistry and Loker Hydrocarbon Research Institute, University of Southern California, Los Angeles, California 90089, United States.
Abstract:
There is an urgent need for improved therapy to better control the ongoing COVID-19 pandemic. The main protease Mpro plays a pivotal role in SARS-CoV-2 replications, thereby representing an attractive target for antiviral development. We seek to identify novel electrophilic warheads for efficient, covalent inhibition of Mpro. By comparing the efficacy of a panel of warheads installed on a common scaffold against Mpro, we discovered that the terminal alkyne could covalently modify Mpro as a latent warhead. Our biochemical and X-ray structural analyses revealed the irreversible formation of the vinyl-sulfide linkage between the alkyne and the catalytic cysteine of Mpro. Clickable probes based on the alkyne inhibitors were developed to measure target engagement, drug residence time, and off-target effects. The best alkyne-containing inhibitors potently inhibited SARS-CoV-2 infection in cell infection models. Our findings highlight great potentials of alkyne as a latent warhead to target cystine proteases in viruses and beyond.
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