From nicotine to SARS-CoV-2 antivirals with potent in vivo efficacy and a broad anti-coronavirus spectrum

TL;DR

Scientists found nicotine-derived compounds that are more effective than Paxlovid against SARS-CoV-2 and other coronaviruses, including resistant variants.

Contribution

Discovery of nicotine-derived MPro inhibitors with superior in vivo efficacy and broad anti-coronavirus activity.

Findings

3-Vinylpyridine inhibits SARS-CoV-2 MPro without relying on the E166 interaction.

Lead compounds YR-C-136 and SR-B-103 show better antiviral efficacy in mice than nirmatrelvir.

Compounds remain effective against nirmatrelvir-resistant MPro variants and other coronaviruses.

Abstract

Anecdotal reports about smoking that might prevent SARS-CoV-2 infection inspire the search for nicotine and its pyrolysis products as inhibitors of the SARS-CoV-2 main protease (MPro). This effort leads to the discovery of 3-vinylpyridine as an MPro inhibitor. 3-Vinylpyridine resembles part of nirmatrelvir in binding to MPro but does not involve a critical interaction with residue E166, whose mutation has led to resistance to nirmatrelvir. Integration of the two molecules, followed by a medicinal chemistry campaign, produces several molecules with better in vitro potency than nirmatrelvir. Two lead molecules, YR-C-136 and SR-B-103, display better pharmacokinetic characteristics than nirmatrelvir in virus-challenged male mice and much better antiviral efficacy in virus-challenged female mice. Both molecules maintain high potency in inhibiting the nirmatrelvir-resistant MPro (E166V/L50F) variant. They also exhibit a broad and highly potent antiviral spectrum against most pathogenic coronaviruses. With high in vivo potency, both molecules are potentially standalone pan-antivirals for coronaviruses and may serve as countermeasures for future coronavirus outbreaks.

Here the authors identify nicotine-derived inhibitors of the SARS-CoV−2 main protease that outperform Paxlovid in cells and mice, remain effective against resistant variants, and show broad activity against multiple human coronaviruses.

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