tetano
Editor, Senior Moderator
Sci Adv
. 2025 Oct 3;11(40):eadz5913.
doi: 10.1126/sciadv.adz5913. Epub 2025 Oct 3. 1'-Cyanocytidine-5'-isobutyryl is a potent SARS-CoV-2 inhibitor in culture and infected Syrian hamsters
Franck Amblard[SUP] 1 [/SUP], Mahesh Kasthuri[SUP] 1 [/SUP], Julia C LeCher[SUP] 1 [/SUP], Sijia Tao[SUP] 1 [/SUP], Ramyani De[SUP] 1 [/SUP], Rana Abdelnabi[SUP] 2 3 [/SUP], Ingrid Marko[SUP] 4 [/SUP], Longhu Zhou[SUP] 1 [/SUP], Chengwei Li[SUP] 1 [/SUP], Junxing Shi[SUP] 1 [/SUP], Shu Ling Goh[SUP] 1 [/SUP], Jessica Downs-Bowen[SUP] 1 [/SUP], Leda Bassit[SUP] 1 [/SUP], Selwyn Hurwitz[SUP] 1 [/SUP], Keivan Zandi[SUP] 1 [/SUP], Tamara McBrayer[SUP] 1 [/SUP], Birgit Weynand[SUP] 5 [/SUP], Kenneth A Johnson[SUP] 4 [/SUP], Johan Neyts[SUP] 2 3 [/SUP], Raymond F Schinazi[SUP] 1 [/SUP]
Affiliations
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and COVID-19 epidemic is relatively under control due to the rapid development and deployment of vaccines and a few drugs. However, challenges persist, as new variants and issues with vaccine durability may compromise their effectiveness. Here, we report the discovery and evaluation of 1'-cyanocytidine (CNC), a nontoxic, next-generation nucleoside analog that displays submicromolar inhibition of SARS-CoV-2 replication in various cell and 3D HAE-ALI primary culture systems. Intracellularly, CNC is metabolized to its active 5'-triphosphate form (CNC-TP), targeting the viral RNA-dependent RNA polymerase. Pre-steady-state kinetic analysis revealed CNC-TP is a reversible, competitive inhibitor. The 5'-isobutyryl ester prodrug of CNC (CNiBuC), which rapidly converts to CNC in mouse and hamster plasma, substantially reduced viral RNA levels and lung infectious virus titers in a Syrian hamster model after intraperitoneal and oral dosing. With favorable pharmacokinetics, bioavailability, and safety profiles, CNC and CNiBuC represent promising candidates for SARS-CoV-2 therapy.
. 2025 Oct 3;11(40):eadz5913.
doi: 10.1126/sciadv.adz5913. Epub 2025 Oct 3. 1'-Cyanocytidine-5'-isobutyryl is a potent SARS-CoV-2 inhibitor in culture and infected Syrian hamsters
Franck Amblard[SUP] 1 [/SUP], Mahesh Kasthuri[SUP] 1 [/SUP], Julia C LeCher[SUP] 1 [/SUP], Sijia Tao[SUP] 1 [/SUP], Ramyani De[SUP] 1 [/SUP], Rana Abdelnabi[SUP] 2 3 [/SUP], Ingrid Marko[SUP] 4 [/SUP], Longhu Zhou[SUP] 1 [/SUP], Chengwei Li[SUP] 1 [/SUP], Junxing Shi[SUP] 1 [/SUP], Shu Ling Goh[SUP] 1 [/SUP], Jessica Downs-Bowen[SUP] 1 [/SUP], Leda Bassit[SUP] 1 [/SUP], Selwyn Hurwitz[SUP] 1 [/SUP], Keivan Zandi[SUP] 1 [/SUP], Tamara McBrayer[SUP] 1 [/SUP], Birgit Weynand[SUP] 5 [/SUP], Kenneth A Johnson[SUP] 4 [/SUP], Johan Neyts[SUP] 2 3 [/SUP], Raymond F Schinazi[SUP] 1 [/SUP]
Affiliations
- PMID: 41042868
- PMCID: PMC12494030
- DOI: 10.1126/sciadv.adz5913
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and COVID-19 epidemic is relatively under control due to the rapid development and deployment of vaccines and a few drugs. However, challenges persist, as new variants and issues with vaccine durability may compromise their effectiveness. Here, we report the discovery and evaluation of 1'-cyanocytidine (CNC), a nontoxic, next-generation nucleoside analog that displays submicromolar inhibition of SARS-CoV-2 replication in various cell and 3D HAE-ALI primary culture systems. Intracellularly, CNC is metabolized to its active 5'-triphosphate form (CNC-TP), targeting the viral RNA-dependent RNA polymerase. Pre-steady-state kinetic analysis revealed CNC-TP is a reversible, competitive inhibitor. The 5'-isobutyryl ester prodrug of CNC (CNiBuC), which rapidly converts to CNC in mouse and hamster plasma, substantially reduced viral RNA levels and lung infectious virus titers in a Syrian hamster model after intraperitoneal and oral dosing. With favorable pharmacokinetics, bioavailability, and safety profiles, CNC and CNiBuC represent promising candidates for SARS-CoV-2 therapy.