1. Discovery of C -Linked Nucleoside Analogues with Antiviral Activity against SARS-CoV-2.
- Author
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Mesaros EF, Dugan BJ, Gao M, Sheraz M, McGovern-Gooch K, Xu F, Fan KY, Nguyen D, Kultgen SG, Lindstrom A, Stever K, Tercero B, Binder RJ, Liu F, Micolochick Steuer HM, Mani N, Harasym TO, Thi EP, Cuconati A, Dorsey BD, Cole AG, Lam AM, and Sofia MJ
- Subjects
- Humans, Animals, Drug Discovery, Viral Nonstructural Proteins antagonists & inhibitors, Viral Nonstructural Proteins metabolism, Chlorocebus aethiops, Vero Cells, COVID-19 virology, Coronavirus RNA-Dependent RNA Polymerase, Antiviral Agents pharmacology, Antiviral Agents chemistry, SARS-CoV-2 drug effects, Nucleosides pharmacology, Nucleosides chemistry, COVID-19 Drug Treatment
- Abstract
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 and ensitrelvir, along with two existing nucleos(t)ide analogues repurposed as nsp12 polymerase inhibitors, remdesivir and molnupiravir, but a need still exists for therapies with improved potency and systemic exposure with oral dosing, better metabolic stability, and reduced resistance and toxicity risks. Herein, we summarize our research toward identifying nsp12 inhibitors that led to nucleoside analogues 10e and 10n , which showed favorable pan-coronavirus activity in cell-infection screens, were metabolized to active triphosphate nucleotides in cell-incubation studies, and demonstrated target (nsp12) engagement in biochemical assays.
- Published
- 2024
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