tetano
Editor, Senior Moderator
Sci Adv
. 2025 Apr 25;11(17):eadt7836.
doi: 10.1126/sciadv.adt7836. Epub 2025 Apr 23. Structure-based discovery of highly bioavailable, covalent, broad-spectrum coronavirus M[SUP]Pro[/SUP] inhibitors with potent in vivo efficacy
Tyler C Detomasi[SUP] 1 [/SUP], Gilles Degotte[SUP] 1 [/SUP], Sijie Huang[SUP] 1 [/SUP], Rahul K Suryawanshi[SUP] 2 [/SUP], Amy Diallo[SUP] 3 [/SUP], Luca Lizzadro[SUP] 1 [/SUP], Francisco J Zaptero-Belinchón[SUP] 2 [/SUP], Taha Y Taha[SUP] 2 [/SUP], Jiapeng Li[SUP] 1 [/SUP], Alicia L Richards[SUP] 4 5 6 [/SUP], Eric R Hantz[SUP] 1 [/SUP], Zain Alam[SUP] 1 [/SUP], Mauricio Montano[SUP] 2 [/SUP], Maria McCavitt-Malvido[SUP] 2 [/SUP], Rajesh Gumpena[SUP] 3 [/SUP], James R Partridge[SUP] 3 [/SUP], Galen J Correy[SUP] 5 [/SUP], Yusuke Matsui[SUP] 2 [/SUP], Annemarie F Charvat[SUP] 1 [/SUP], Isabella S Glenn[SUP] 1 [/SUP], Julia Rosecrans[SUP] 2 [/SUP], Jezrael L Revalde[SUP] 1 [/SUP], Dashiell Anderson[SUP] 1 [/SUP], Judd F Hultquist[SUP] 7 [/SUP], Michelle R Arkin[SUP] 1 [/SUP], R Jeffrey Neitz[SUP] 1 [/SUP], Danielle L Swaney[SUP] 3 4 6 [/SUP], Nevan J Krogan[SUP] 4 5 6 [/SUP], Brian K Shoichet[SUP] 1 [/SUP], Kliment A Verba[SUP] 3 6 [/SUP], Melanie Ott[SUP] 2 [/SUP], Adam R Renslo[SUP] 1 [/SUP], Charles S Craik[SUP] 1 [/SUP]
Affiliations
The main protease (M[SUP]Pro[/SUP]) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a validated drug target. Starting with a lead-like dihydrouracil chemotype identified in a large-library docking campaign, we improved M[SUP]Pro[/SUP] inhibition >1000-fold by engaging additional M[SUP]Pro[/SUP] subsites and using a latent electrophile to engage Cys[SUP]145[/SUP]. Advanced leads from this series show pan-coronavirus antiviral activity, low clearance in mice, and for AVI-4773, a rapid reduction in viral titers >1,000,000 after just three doses. Both compounds are well distributed in mouse tissues, including brain, where concentrations >1000× the 90% effective concentration are observed 8 hours after oral dosing for AVI-4773. AVI-4516 shows minimal inhibition of major cytochrome P450s and human proteases. AVI-4516 also exhibits synergy with the RNA-dependent RNA polymerase inhibitor, molnupiravir, in cellular infection models. Related analogs strongly inhibit nirmatrelvir-resistant M[SUP]Pro[/SUP] mutant virus. The properties of this chemotype are differentiated from existing clinical and preclinical M[SUP]Pro[/SUP] inhibitors and will advance therapeutic development against emerging SARS-CoV-2 variants and other coronaviruses.
. 2025 Apr 25;11(17):eadt7836.
doi: 10.1126/sciadv.adt7836. Epub 2025 Apr 23. Structure-based discovery of highly bioavailable, covalent, broad-spectrum coronavirus M[SUP]Pro[/SUP] inhibitors with potent in vivo efficacy
Tyler C Detomasi[SUP] 1 [/SUP], Gilles Degotte[SUP] 1 [/SUP], Sijie Huang[SUP] 1 [/SUP], Rahul K Suryawanshi[SUP] 2 [/SUP], Amy Diallo[SUP] 3 [/SUP], Luca Lizzadro[SUP] 1 [/SUP], Francisco J Zaptero-Belinchón[SUP] 2 [/SUP], Taha Y Taha[SUP] 2 [/SUP], Jiapeng Li[SUP] 1 [/SUP], Alicia L Richards[SUP] 4 5 6 [/SUP], Eric R Hantz[SUP] 1 [/SUP], Zain Alam[SUP] 1 [/SUP], Mauricio Montano[SUP] 2 [/SUP], Maria McCavitt-Malvido[SUP] 2 [/SUP], Rajesh Gumpena[SUP] 3 [/SUP], James R Partridge[SUP] 3 [/SUP], Galen J Correy[SUP] 5 [/SUP], Yusuke Matsui[SUP] 2 [/SUP], Annemarie F Charvat[SUP] 1 [/SUP], Isabella S Glenn[SUP] 1 [/SUP], Julia Rosecrans[SUP] 2 [/SUP], Jezrael L Revalde[SUP] 1 [/SUP], Dashiell Anderson[SUP] 1 [/SUP], Judd F Hultquist[SUP] 7 [/SUP], Michelle R Arkin[SUP] 1 [/SUP], R Jeffrey Neitz[SUP] 1 [/SUP], Danielle L Swaney[SUP] 3 4 6 [/SUP], Nevan J Krogan[SUP] 4 5 6 [/SUP], Brian K Shoichet[SUP] 1 [/SUP], Kliment A Verba[SUP] 3 6 [/SUP], Melanie Ott[SUP] 2 [/SUP], Adam R Renslo[SUP] 1 [/SUP], Charles S Craik[SUP] 1 [/SUP]
Affiliations
- PMID: 40267184
- DOI: 10.1126/sciadv.adt7836
The main protease (M[SUP]Pro[/SUP]) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a validated drug target. Starting with a lead-like dihydrouracil chemotype identified in a large-library docking campaign, we improved M[SUP]Pro[/SUP] inhibition >1000-fold by engaging additional M[SUP]Pro[/SUP] subsites and using a latent electrophile to engage Cys[SUP]145[/SUP]. Advanced leads from this series show pan-coronavirus antiviral activity, low clearance in mice, and for AVI-4773, a rapid reduction in viral titers >1,000,000 after just three doses. Both compounds are well distributed in mouse tissues, including brain, where concentrations >1000× the 90% effective concentration are observed 8 hours after oral dosing for AVI-4773. AVI-4516 shows minimal inhibition of major cytochrome P450s and human proteases. AVI-4516 also exhibits synergy with the RNA-dependent RNA polymerase inhibitor, molnupiravir, in cellular infection models. Related analogs strongly inhibit nirmatrelvir-resistant M[SUP]Pro[/SUP] mutant virus. The properties of this chemotype are differentiated from existing clinical and preclinical M[SUP]Pro[/SUP] inhibitors and will advance therapeutic development against emerging SARS-CoV-2 variants and other coronaviruses.