tetano
Editor, Senior Moderator
Nat Commun
. 2026 Feb 14.
doi: 10.1038/s41467-026-69527-5. Online ahead of print.
From nicotine to SARS-CoV-2 antivirals with potent in vivo efficacy and a broad anti-coronavirus spectrum
Kaustav Khatua[SUP] #[/SUP][SUP] 1 [/SUP], Sandeep Atla[SUP] #[/SUP][SUP] 1 [/SUP], Demonta Coleman[SUP] #[/SUP][SUP] 1 [/SUP], Lauren R Blankenship[SUP] #[/SUP][SUP] 1 [/SUP], Yugendar R Alugubelli[SUP] #[/SUP][SUP] 1 [/SUP], Veerabhadra Vulupala[SUP] #[/SUP][SUP] 1 [/SUP], Xuejiao Shirley Guo[SUP] 1 [/SUP], Hongjie Xia[SUP] 2 [/SUP], Birte K Kalveram[SUP] 2 [/SUP], David H Walker[SUP] 3 [/SUP], Brett L Hurst[SUP] 4 [/SUP], Sathish Kumar[SUP] 5 [/SUP], Chia-Chuan D Cho[SUP] 1 [/SUP], Shivangi Sharma[SUP] 1 [/SUP], Kai Yang[SUP] 1 [/SUP], Dorsa Rabie[SUP] 1 [/SUP], Satyanarayana Nyalata[SUP] 1 [/SUP], Benjamin W Neuman[SUP] 6 [/SUP], Xuping Xie[SUP] 7 8 [/SUP], Shiqing Xu[SUP] 9 10 [/SUP], Wenshe Ray Liu[SUP] 11 12 13 14 15 [/SUP]
Affiliations
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 (M[SUP]Pro[/SUP]). This effort leads to the discovery of 3-vinylpyridine as an M[SUP]Pro[/SUP] inhibitor. 3-Vinylpyridine resembles part of nirmatrelvir in binding to M[SUP]Pro[/SUP] 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 M[SUP]Pro[/SUP] (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.
. 2026 Feb 14.
doi: 10.1038/s41467-026-69527-5. Online ahead of print.
From nicotine to SARS-CoV-2 antivirals with potent in vivo efficacy and a broad anti-coronavirus spectrum
Kaustav Khatua[SUP] #[/SUP][SUP] 1 [/SUP], Sandeep Atla[SUP] #[/SUP][SUP] 1 [/SUP], Demonta Coleman[SUP] #[/SUP][SUP] 1 [/SUP], Lauren R Blankenship[SUP] #[/SUP][SUP] 1 [/SUP], Yugendar R Alugubelli[SUP] #[/SUP][SUP] 1 [/SUP], Veerabhadra Vulupala[SUP] #[/SUP][SUP] 1 [/SUP], Xuejiao Shirley Guo[SUP] 1 [/SUP], Hongjie Xia[SUP] 2 [/SUP], Birte K Kalveram[SUP] 2 [/SUP], David H Walker[SUP] 3 [/SUP], Brett L Hurst[SUP] 4 [/SUP], Sathish Kumar[SUP] 5 [/SUP], Chia-Chuan D Cho[SUP] 1 [/SUP], Shivangi Sharma[SUP] 1 [/SUP], Kai Yang[SUP] 1 [/SUP], Dorsa Rabie[SUP] 1 [/SUP], Satyanarayana Nyalata[SUP] 1 [/SUP], Benjamin W Neuman[SUP] 6 [/SUP], Xuping Xie[SUP] 7 8 [/SUP], Shiqing Xu[SUP] 9 10 [/SUP], Wenshe Ray Liu[SUP] 11 12 13 14 15 [/SUP]
Affiliations
- PMID: 41690944
- DOI: 10.1038/s41467-026-69527-5
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 (M[SUP]Pro[/SUP]). This effort leads to the discovery of 3-vinylpyridine as an M[SUP]Pro[/SUP] inhibitor. 3-Vinylpyridine resembles part of nirmatrelvir in binding to M[SUP]Pro[/SUP] 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 M[SUP]Pro[/SUP] (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.