tetano
Editor, Senior Moderator
J Med Chem
. 2026 Feb 9.
doi: 10.1021/acs.jmedchem.5c02360. Online ahead of print.
Discovery of EGT710, an Oral Nonpeptidomimetic Reversible Covalent SARS-CoV-2 Main Protease Inhibitor
Julien P N Papillon[SUP] 1 [/SUP], Jun Yuan[SUP] 1 [/SUP], Matthew J Hesse[SUP] 2 [/SUP], Lei Zhang[SUP] 2 [/SUP], Richard I Robinson[SUP] 1 [/SUP], Nathaniel F Ware[SUP] 1 [/SUP], Viktor Hornak[SUP] 1 [/SUP], Rajeshri G Karki[SUP] 1 [/SUP], Tom Kirrane[SUP] 2 [/SUP], Keira Garland[SUP] 2 [/SUP], Sajan Joseph[SUP] 1 [/SUP], Stephanie A Moquin[SUP] 3 4 [/SUP], Suresh B Lakshminarayana[SUP] 5 [/SUP], Laura Tandeske[SUP] 3 [/SUP], Dustin Dovala[SUP] 3 [/SUP], Mark Knapp[SUP] 3 [/SUP], Elizabeth Ornelas[SUP] 3 [/SUP], Daniel Fuller[SUP] 6 [/SUP], Pei-I Ho[SUP] 6 [/SUP], Xuping Xie[SUP] 7 [/SUP], Katarina Vulic[SUP] 8 [/SUP], Suzanne M Skolnik[SUP] 1 [/SUP], Jinhai Gao[SUP] 1 [/SUP], Mark Zambrowski[SUP] 1 [/SUP], Meike Spiess[SUP] 1 [/SUP], José S Duca[SUP] 1 [/SUP], Scott A Busby[SUP] 6 [/SUP], Markus Schirle[SUP] 6 [/SUP], Michael Robinson[SUP] 4 [/SUP], Pei-Yong Shi[SUP] 7 [/SUP], Heinz E Moser[SUP] 1 [/SUP], Christopher Sarko[SUP] 2 [/SUP], James E Bradner[SUP] 9 [/SUP], Thierry T Diagana[SUP] 3 [/SUP], John A Tallarico[SUP] 6 [/SUP]
Affiliations
The coronavirus main protease (3CL[SUP]pro[/SUP], M[SUP]pro[/SUP], nsp5) is a highly conserved cysteine protease unique to the Coronaviridae family, including SARS-CoV-2, and is a validated target for the treatment of COVID-19. Our efforts focused on the identification of a nonpeptidomimetic M[SUP]pro[/SUP] inhibitor, due to the potential for superior pharmacological properties. Herein, we report our efforts leveraging virtual screening and X-ray crystallography that enabled a structure-based drug design approach, leading to the discovery of series of quinazoline-2,4(1H,3H)-dione and oxoimidazolidine-4-carbonitrile compounds with potent inhibition of SARS-CoV-2 M[SUP]pro[/SUP] as well as other coronaviruses main proteases. Extensive lead optimization focusing on pharmacokinetic properties, developability, and breadth of activity across coronaviruses, led to the identification of EGT710. EGT710 demonstrates excellent potency against SARS-CoV-2 infection in a primary differentiated normal human bronchial epithelial (dNHBE) cellular assay, as well as a favorable pharmacology profile that supported advancement into preclinical and clinical studies.
. 2026 Feb 9.
doi: 10.1021/acs.jmedchem.5c02360. Online ahead of print.
Discovery of EGT710, an Oral Nonpeptidomimetic Reversible Covalent SARS-CoV-2 Main Protease Inhibitor
Julien P N Papillon[SUP] 1 [/SUP], Jun Yuan[SUP] 1 [/SUP], Matthew J Hesse[SUP] 2 [/SUP], Lei Zhang[SUP] 2 [/SUP], Richard I Robinson[SUP] 1 [/SUP], Nathaniel F Ware[SUP] 1 [/SUP], Viktor Hornak[SUP] 1 [/SUP], Rajeshri G Karki[SUP] 1 [/SUP], Tom Kirrane[SUP] 2 [/SUP], Keira Garland[SUP] 2 [/SUP], Sajan Joseph[SUP] 1 [/SUP], Stephanie A Moquin[SUP] 3 4 [/SUP], Suresh B Lakshminarayana[SUP] 5 [/SUP], Laura Tandeske[SUP] 3 [/SUP], Dustin Dovala[SUP] 3 [/SUP], Mark Knapp[SUP] 3 [/SUP], Elizabeth Ornelas[SUP] 3 [/SUP], Daniel Fuller[SUP] 6 [/SUP], Pei-I Ho[SUP] 6 [/SUP], Xuping Xie[SUP] 7 [/SUP], Katarina Vulic[SUP] 8 [/SUP], Suzanne M Skolnik[SUP] 1 [/SUP], Jinhai Gao[SUP] 1 [/SUP], Mark Zambrowski[SUP] 1 [/SUP], Meike Spiess[SUP] 1 [/SUP], José S Duca[SUP] 1 [/SUP], Scott A Busby[SUP] 6 [/SUP], Markus Schirle[SUP] 6 [/SUP], Michael Robinson[SUP] 4 [/SUP], Pei-Yong Shi[SUP] 7 [/SUP], Heinz E Moser[SUP] 1 [/SUP], Christopher Sarko[SUP] 2 [/SUP], James E Bradner[SUP] 9 [/SUP], Thierry T Diagana[SUP] 3 [/SUP], John A Tallarico[SUP] 6 [/SUP]
Affiliations
- PMID: 41663073
- DOI: 10.1021/acs.jmedchem.5c02360
The coronavirus main protease (3CL[SUP]pro[/SUP], M[SUP]pro[/SUP], nsp5) is a highly conserved cysteine protease unique to the Coronaviridae family, including SARS-CoV-2, and is a validated target for the treatment of COVID-19. Our efforts focused on the identification of a nonpeptidomimetic M[SUP]pro[/SUP] inhibitor, due to the potential for superior pharmacological properties. Herein, we report our efforts leveraging virtual screening and X-ray crystallography that enabled a structure-based drug design approach, leading to the discovery of series of quinazoline-2,4(1H,3H)-dione and oxoimidazolidine-4-carbonitrile compounds with potent inhibition of SARS-CoV-2 M[SUP]pro[/SUP] as well as other coronaviruses main proteases. Extensive lead optimization focusing on pharmacokinetic properties, developability, and breadth of activity across coronaviruses, led to the identification of EGT710. EGT710 demonstrates excellent potency against SARS-CoV-2 infection in a primary differentiated normal human bronchial epithelial (dNHBE) cellular assay, as well as a favorable pharmacology profile that supported advancement into preclinical and clinical studies.