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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 MPro inhibitors with potent in vivo efficacy
Tyler C Detomasi 1 , Gilles Degotte 1 , Sijie Huang 1 , Rahul K Suryawanshi 2 , Amy Diallo 3 , Luca Lizzadro 1 , Francisco J Zaptero-Belinchón 2 , Taha Y Taha 2 , Jiapeng Li 1 , Alicia L Richards 4 5 6 , Eric R Hantz 1 , Zain Alam 1 , Mauricio Montano 2 , Maria McCavitt-Malvido 2 , Rajesh Gumpena 3 , James R Partridge 3 , Galen J Correy 5 , Yusuke Matsui 2 , Annemarie F Charvat 1 , Isabella S Glenn 1 , Julia Rosecrans 2 , Jezrael L Revalde 1 , Dashiell Anderson 1 , Judd F Hultquist 7 , Michelle R Arkin 1 , R Jeffrey Neitz 1 , Danielle L Swaney 3 4 6 , Nevan J Krogan 4 5 6 , Brian K Shoichet 1 , Kliment A Verba 3 6 , Melanie Ott 2 , Adam R Renslo 1 , Charles S Craik 1
Affiliations
The main protease (MPro) 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 MPro inhibition >1000-fold by engaging additional MPro subsites and using a latent electrophile to engage Cys145. 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 MPro mutant virus. The properties of this chemotype are differentiated from existing clinical and preclinical MPro 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 MPro inhibitors with potent in vivo efficacy
Tyler C Detomasi 1 , Gilles Degotte 1 , Sijie Huang 1 , Rahul K Suryawanshi 2 , Amy Diallo 3 , Luca Lizzadro 1 , Francisco J Zaptero-Belinchón 2 , Taha Y Taha 2 , Jiapeng Li 1 , Alicia L Richards 4 5 6 , Eric R Hantz 1 , Zain Alam 1 , Mauricio Montano 2 , Maria McCavitt-Malvido 2 , Rajesh Gumpena 3 , James R Partridge 3 , Galen J Correy 5 , Yusuke Matsui 2 , Annemarie F Charvat 1 , Isabella S Glenn 1 , Julia Rosecrans 2 , Jezrael L Revalde 1 , Dashiell Anderson 1 , Judd F Hultquist 7 , Michelle R Arkin 1 , R Jeffrey Neitz 1 , Danielle L Swaney 3 4 6 , Nevan J Krogan 4 5 6 , Brian K Shoichet 1 , Kliment A Verba 3 6 , Melanie Ott 2 , Adam R Renslo 1 , Charles S Craik 1
Affiliations
- PMID: 40267184
- DOI: 10.1126/sciadv.adt7836
The main protease (MPro) 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 MPro inhibition >1000-fold by engaging additional MPro subsites and using a latent electrophile to engage Cys145. 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 MPro mutant virus. The properties of this chemotype are differentiated from existing clinical and preclinical MPro inhibitors and will advance therapeutic development against emerging SARS-CoV-2 variants and other coronaviruses.