Discovery of C-Linked Nucleoside Analogues with Antiviral Activity against SARS-CoV-2

• DOI: 10.1021/acsinfecdis.4c00122
• Publication Date: 2024-04-23T11:50:33Z
• Authors: Eugen F. Mesaros; Benjamin J. Dugan; Min Gao; Muhammad Sheraz; Kayleigh McGovern...; Fran Xu; Kristi Yi Fan; Duyan Nguyen; Steven G. Kultgen; Aaron Lindstrom; Kim Stever; Breanna Tercero; Randall J. Binder; Fei Liu; Holly M. Micoloch...; Nagraj Mani; Troy O. Harasym; Emily P. Thi; Andrea Cuconati; Bruce D. Dorsey; Andrew G. Cole; Angela M. Lam; Michael J. Sofia
• Keywords: 2019-20 coronavirus outbreak; Nucleoside analogue; Antiviral drug; Sars virus

The recent COVID-19 pandemic underscored the limitations of currently available direct-acting antiviral treatments against acute respiratory RNA-viral infections and stimulated major research initiatives targeting anticoronavirus agents. Two novel nsp5 protease (MPro) inhibitors have been approved, nirmatrelvir ensitrelvir, along with two existing nucleos(t)ide analogues repurposed as nsp12 polymerase inhibitors, remdesivir molnupiravir, but a need still exists for therapies improved potency systemic exposure oral dosing, better metabolic stability, reduced resistance toxicity risks. Herein, we summarize our toward identifying that led to nucleoside 10e 10n, which showed favorable pan-coronavirus activity in cell-infection screens, were metabolized active triphosphate nucleotides cell-incubation studies, demonstrated target (nsp12) engagement biochemical assays.