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.
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Data availability
All data are available in the main text or the supplementary materials. The crystal structures for MPro complexed with various inhibitors have been deposited into the Protein Data Bank with the following entry codes: 9BS7 (VP), 9BTT (SR-B-51), 9BTF (SR-B-77), 9P6F (SR-B-78), 9BTK (YR-C-108), 9BVW (SR-B-103), 9BVX (YR-C-155), and 9BSR (R-C-136). The source data underlying Figs. 4, 5, and Table 1, Table S2 are provided as a Source Data file. Viral resistance profile data access codes in NCBI SRA: SRR37076225 (wild-type SARS-CoV-2 sequence reads), SRR37076230-SRR37076233 (four biological repeats for SR-B-103 treated viruses), and SRR37076226-SRR37076229 (four biological repeats for YR-C-136 treated viruses). Source data are provided with this paper.
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Acknowledgements
We thank Dr. Yohannes Rezenom in the Mass Spectrometry Facility and Prof. Xin Yan of Texas A&M University for helping with the LC-MS characterizations of inhibitors. Funding: National Institutes of Health grant R35GM145351 (W.R.L.). National Institutes of Health grant R21AI164088 (S.X.). National Institutes of Health Grant R21EB032983 (W.R.L.). Welch Foundation Grant A-1715 (W.R.L.). Welch Foundation Grant A-2174 (S.X.). Texas A&M University Advancing Discovery to Market Grant (W.R.L., S.X.). Texas A&M X Grants (W.R.L., S.X.). This work was partially supported by Task Order 75N93024F00002 under Contract 75N93019D00021 from the Respiratory Diseases Branch of the National Institute of Allergy and Infectious Diseases.
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W.R.L., S.X., X.X., and B.W.N. conceived and supervised the research; W.R.L. and S.X. designed all inhibitors; S.A., Y.R.A., V.V., and S.N. synthesized the inhibitors and performed their purification and characterizations; K.K. conducted enzymatic IC50 characterizations of the inhibitors; K.K. and X.S.G. performed in vitro PK analysis of selected inhibitors; D.C. and C.-C.D.C. performed characterizations of cellular IC50 values to engage MPro expressed in HEK293T cells; S.S. and C.-C.D.C. expressed and purified MPro (E166V/L50F), SARS-CoV MPro, and MERS-CoV MPro; L.R.B., K.Y., and D.R. conducted the X-ray protein crystallography analysis; S.K. characterized antiviral potency of inhibitors in cell culture; H.X. and B.K.K. conducted in vivo antiviral studies and mouse tissue analysis, D.H.W. performed the histopathologic analysis and scoring; B.L.H. conducted the in vitro antiviral potency test on SARS-CoV-2 USA_WA1/2020, SARS-CoV-2 Delta B.1.617.2 AY.4, SARS-CoV-2 Omicron BQ.1, HCoV-Alpha 229E, HCoV-Beta OC43, SARS Urbani, and MERS-CoV EMC variants. All authors participated in data analysis. W.R.L., S.X., X.X., and B.W.N. drafted the manuscript with the assistance of K.K., D.C., S.A., Y.R.A., V.V., and L.R.B.
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Khatua, K., Atla, S., Coleman, D. et al. From nicotine to SARS-CoV-2 antivirals with potent in vivo efficacy and a broad anti-coronavirus spectrum. Nat Commun (2026). https://doi.org/10.1038/s41467-026-69527-5
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DOI: https://doi.org/10.1038/s41467-026-69527-5
