tetano
Editor, Senior Moderator
ACS Infect Dis
. 2024 Apr 23.
doi: 10.1021/acsinfecdis.4c00122. Online ahead of print. Discovery of C-Linked Nucleoside Analogues with Antiviral Activity against SARS-CoV-2
Eugen F Mesaros[SUP] 1 [/SUP], Benjamin J Dugan[SUP] 1 [/SUP], Min Gao[SUP] 1 [/SUP], Muhammad Sheraz[SUP] 1 [/SUP], Kayleigh McGovern-Gooch[SUP] 1 [/SUP], Fran Xu[SUP] 1 [/SUP], Kristi Yi Fan[SUP] 1 [/SUP], Duyan Nguyen[SUP] 1 [/SUP], Steven G Kultgen[SUP] 1 [/SUP], Aaron Lindstrom[SUP] 1 [/SUP], Kim Stever[SUP] 1 [/SUP], Breanna Tercero[SUP] 1 [/SUP], Randall J Binder[SUP] 1 [/SUP], Fei Liu[SUP] 1 [/SUP], Holly M Micolochick Steuer[SUP] 1 [/SUP], Nagraj Mani[SUP] 1 [/SUP], Troy O Harasym[SUP] 1 [/SUP], Emily P Thi[SUP] 1 [/SUP], Andrea Cuconati[SUP] 1 [/SUP], Bruce D Dorsey[SUP] 1 [/SUP], Andrew G Cole[SUP] 1 [/SUP], Angela M Lam[SUP] 1 [/SUP], Michael J Sofia[SUP] 1 [/SUP]
Affiliations
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.
. 2024 Apr 23.
doi: 10.1021/acsinfecdis.4c00122. Online ahead of print. Discovery of C-Linked Nucleoside Analogues with Antiviral Activity against SARS-CoV-2
Eugen F Mesaros[SUP] 1 [/SUP], Benjamin J Dugan[SUP] 1 [/SUP], Min Gao[SUP] 1 [/SUP], Muhammad Sheraz[SUP] 1 [/SUP], Kayleigh McGovern-Gooch[SUP] 1 [/SUP], Fran Xu[SUP] 1 [/SUP], Kristi Yi Fan[SUP] 1 [/SUP], Duyan Nguyen[SUP] 1 [/SUP], Steven G Kultgen[SUP] 1 [/SUP], Aaron Lindstrom[SUP] 1 [/SUP], Kim Stever[SUP] 1 [/SUP], Breanna Tercero[SUP] 1 [/SUP], Randall J Binder[SUP] 1 [/SUP], Fei Liu[SUP] 1 [/SUP], Holly M Micolochick Steuer[SUP] 1 [/SUP], Nagraj Mani[SUP] 1 [/SUP], Troy O Harasym[SUP] 1 [/SUP], Emily P Thi[SUP] 1 [/SUP], Andrea Cuconati[SUP] 1 [/SUP], Bruce D Dorsey[SUP] 1 [/SUP], Andrew G Cole[SUP] 1 [/SUP], Angela M Lam[SUP] 1 [/SUP], Michael J Sofia[SUP] 1 [/SUP]
Affiliations
- PMID: 38651692
- DOI: 10.1021/acsinfecdis.4c00122
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.