2. Academic Validation
  3. Discovery of C-Linked Nucleoside Analogues with Antiviral Activity against SARS-CoV-2

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

  • ACS Infect Dis. 2024 May 10;10(5):1780-1792. doi: 10.1021/acsinfecdis.4c00122.
Eugen F Mesaros 1,  Benjamin J Dugan 1,  Min Gao 1,  Muhammad Sheraz 1,  Kayleigh McGovern-Gooch 1,  Fran Xu 1,  Kristi Yi Fan 1,  Duyan Nguyen 1,  Steven G Kultgen 1,  Aaron Lindstrom 1,  Kim Stever 1,  Breanna Tercero 1,  Randall J Binder 1,  Fei Liu 1,  Holly M Micolochick Steuer 1,  Nagraj Mani 1,  Troy O Harasym 1,  Emily P Thi 1,  Andrea Cuconati 1,  Bruce D Dorsey 1,  Andrew G Cole 1,  Angela M Lam 1,  Michael J Sofia 1
Affiliations

Affiliation

  • 1 Arbutus Biopharma, Inc., 701 Veterans Circle, Warminster, Pennsylvania 18974, United States.
PMID: 38651692 DOI: 10.1021/acsinfecdis.4c00122
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.

Keywords

antiviral agents; coronavirus; inhibitors; nsp12 polymerase; nucleoside analogues.

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