tetano
Editor, Senior Moderator
J Med Chem
. 2026 Jan 5.
doi: 10.1021/acs.jmedchem.5c03015. Online ahead of print. Discovery of Coronavirus Main Protease Inhibitors with Enhanced Brain Exposure and Potent Oral Efficacy in SARS-CoV-2 and MERS Infection Models
Luca Lizzadro[SUP] 1 [/SUP], Jiapeng Li[SUP] 1 [/SUP], Taha Y Taha[SUP] 2 3 [/SUP], Gilles Degotte[SUP] 1 [/SUP], Tyler C Detomasi[SUP] 1 [/SUP], Francisco J Zapatero-Belinchon[SUP] 2 [/SUP], Eric R Hantz[SUP] 1 [/SUP], Sijie Huang[SUP] 1 [/SUP], Yusuke Matsui[SUP] 2 [/SUP], Will R Henderson[SUP] 1 [/SUP], Jack T McCann[SUP] 1 [/SUP], Mauricio Montano[SUP] 2 [/SUP], Julia Rosecrans[SUP] 2 [/SUP], Daniel F Torres Pomares[SUP] 1 [/SUP], Briana L McGovern[SUP] 4 5 [/SUP], Randy Diaz-Tapia[SUP] 4 5 [/SUP], Jared Benjamin[SUP] 4 5 [/SUP], Mary E Gordon[SUP] 4 5 [/SUP], Isidora D Suazo[SUP] 4 5 [/SUP], Nicholas S Settineri[SUP] 6 [/SUP], Amy Diallo[SUP] 7 [/SUP], Nevan J Krogan[SUP] 8 9 [/SUP], Brian K Shoichet[SUP] 1 9 [/SUP], Kliment A Verba[SUP] 7 9 [/SUP], Randy Albrecht[SUP] 4 5 [/SUP], Adolfo García-Sastre[SUP] 4 5 10 11 12 13 [/SUP], Kris M White[SUP] 4 5 [/SUP], Melanie Ott[SUP] 2 14 15 [/SUP], Charles S Craik[SUP] 1 9 [/SUP], Adam R Renslo[SUP] 1 9 [/SUP]
Affiliations
The main proteases (M[SUP]Pro[/SUP]) of coronaviruses are clinically validated targets for antiviral discovery. Herein, we detail the in vivo optimization of uracil-core M[SUP]Pro[/SUP] inhibitors derived from AVI-4516, an in vivo active lead bearing an unactivated propargyl warhead. To expand the anticoronaviral spectrum, we introduced diverse C6 substitution to target the S1' pocket in M[SUP]Pro[/SUP] and observed enhanced cellular activity against various nirmatrelvir-resistant mutants. Pharmacokinetic profiling of 12 analogs revealed overall inferior exposure of the C6 aryl analogs. However, PK profiling across three species identified the improved atropisomeric lead (M)-AVI-4773 (5-(5,6-difluoro-1H-benzo[d][1,2,3]triazol-1-yl)-3-((M)-isoquinolin-4-yl)-6-methyl-1-(prop-2-yn-1-yl)pyrimidine-2,4(1H,3H)-dione), which exhibits rapid-onset oral efficacy in both SARS-CoV-2 and Middle East respiratory syndrome (MERS) mouse models, highlighting a promising chemotype with the potential to deliver anticoronaviral development candidates.
. 2026 Jan 5.
doi: 10.1021/acs.jmedchem.5c03015. Online ahead of print. Discovery of Coronavirus Main Protease Inhibitors with Enhanced Brain Exposure and Potent Oral Efficacy in SARS-CoV-2 and MERS Infection Models
Luca Lizzadro[SUP] 1 [/SUP], Jiapeng Li[SUP] 1 [/SUP], Taha Y Taha[SUP] 2 3 [/SUP], Gilles Degotte[SUP] 1 [/SUP], Tyler C Detomasi[SUP] 1 [/SUP], Francisco J Zapatero-Belinchon[SUP] 2 [/SUP], Eric R Hantz[SUP] 1 [/SUP], Sijie Huang[SUP] 1 [/SUP], Yusuke Matsui[SUP] 2 [/SUP], Will R Henderson[SUP] 1 [/SUP], Jack T McCann[SUP] 1 [/SUP], Mauricio Montano[SUP] 2 [/SUP], Julia Rosecrans[SUP] 2 [/SUP], Daniel F Torres Pomares[SUP] 1 [/SUP], Briana L McGovern[SUP] 4 5 [/SUP], Randy Diaz-Tapia[SUP] 4 5 [/SUP], Jared Benjamin[SUP] 4 5 [/SUP], Mary E Gordon[SUP] 4 5 [/SUP], Isidora D Suazo[SUP] 4 5 [/SUP], Nicholas S Settineri[SUP] 6 [/SUP], Amy Diallo[SUP] 7 [/SUP], Nevan J Krogan[SUP] 8 9 [/SUP], Brian K Shoichet[SUP] 1 9 [/SUP], Kliment A Verba[SUP] 7 9 [/SUP], Randy Albrecht[SUP] 4 5 [/SUP], Adolfo García-Sastre[SUP] 4 5 10 11 12 13 [/SUP], Kris M White[SUP] 4 5 [/SUP], Melanie Ott[SUP] 2 14 15 [/SUP], Charles S Craik[SUP] 1 9 [/SUP], Adam R Renslo[SUP] 1 9 [/SUP]
Affiliations
- PMID: 41490206
- DOI: 10.1021/acs.jmedchem.5c03015
The main proteases (M[SUP]Pro[/SUP]) of coronaviruses are clinically validated targets for antiviral discovery. Herein, we detail the in vivo optimization of uracil-core M[SUP]Pro[/SUP] inhibitors derived from AVI-4516, an in vivo active lead bearing an unactivated propargyl warhead. To expand the anticoronaviral spectrum, we introduced diverse C6 substitution to target the S1' pocket in M[SUP]Pro[/SUP] and observed enhanced cellular activity against various nirmatrelvir-resistant mutants. Pharmacokinetic profiling of 12 analogs revealed overall inferior exposure of the C6 aryl analogs. However, PK profiling across three species identified the improved atropisomeric lead (M)-AVI-4773 (5-(5,6-difluoro-1H-benzo[d][1,2,3]triazol-1-yl)-3-((M)-isoquinolin-4-yl)-6-methyl-1-(prop-2-yn-1-yl)pyrimidine-2,4(1H,3H)-dione), which exhibits rapid-onset oral efficacy in both SARS-CoV-2 and Middle East respiratory syndrome (MERS) mouse models, highlighting a promising chemotype with the potential to deliver anticoronaviral development candidates.