1′-Cyanocytidine-5′-isobutyryl is a potent SARS-CoV-2 inhibitor in culture and infected Syrian hamsters
- Franck Amblard
- Mahesh Kasthuri
- Julia C. LeCher
- Sijia Tao
- Ramyani De
- Rana Abdelnabi
- Ingrid Marko
- Longhu Zhou
- Chengwei Li
- Junxing Shi
- Shu Ling Goh
- Jessica Downs-Bowen
- Leda Bassit
- Selwyn Hurwitz
- Keivan Zandi
- Tamara McBrayer
- Birgit Weynand
- Kenneth A. Johnson
- Johan Neyts
- Raymond F. Schinazi
2025-10-03
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 (CN iBu C), 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 CN iBu C represent promising candidates for SARS-CoV-2 therapy.