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bioRxiv · 10.1101/2024.03.28.587229

Broad-Spectrum Coronavirus Inhibitors Discovered by Modeling Viral Fusion Dynamics

Reilly, C. B.·Moore, J.·Lightbown, S.·Paul, A. J.·Bernier, S. G.·Carlson, K. E.·Ingber, D. D.
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Abstract

Broad-spectrum therapeutics capable of inhibiting SARS-CoV-2, its variants, and related coronaviruses hold promise in curbing the spread of COVID-19 and averting future pandemics. Here, we employed a multidisciplinary approach that included molecular dynamics simulation (MDS) and artificial intelligence (AI)-based docking predictions to identify potent inhibitors that target a conserved region within the SARS-CoV-2 spike protein that mediates membrane fusion by undergoing large-scale mechanical rearrangements. In silico binding screens honed in on this region, leading to the discovery of FDA-approved drugs and novel molecules predicted to disrupt spike protein conformational changes. These compounds significantly inhibited SARS-CoV-2 infection and blocked the entry of spike protein-bearing pseudotyped , {beta}, {gamma}, {delta} variants as well as SARS-CoV and MERS-CoV in cultured human ACE2-expressing cells. The optimized lead compound significantly inhibited SARS-CoV2 infection in mice when administered orally.

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Reilly, C. B., Moore, J., Lightbown, S., Paul, A. J., Bernier, S. G., Carlson, K. E., Ingber, D. D.. 2024-03-29. Broad-Spectrum Coronavirus Inhibitors Discovered by Modeling Viral Fusion Dynamics. https://doi.org/10.1101/2024.03.28.587229

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