AI Article Synopsis
- There is a critical need for better COVID-19 therapies, with the main protease M being an important target for antiviral treatments.
- Researchers identified a terminal alkyne as an effective covalent inhibitor of M, leading to irreversible modification that disrupts the virus's replication.
- The study produced clickable probes to assess how these inhibitors interact with the target, showing that alkyne-containing compounds effectively reduced SARS-CoV-2 infection in lab models.
Article Abstract
There is an urgent need for improved therapy to better control the ongoing COVID-19 pandemic. The main protease M 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 M. By comparing the efficacy of a panel of warheads installed on a common scaffold against M, we discovered that the terminal alkyne could covalently modify M 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 M. 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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Source |
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10510381 | PMC |
| http://dx.doi.org/10.1021/acs.jmedchem.3c00810 | DOI Listing |
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