8HEF

The Crystal structure of deuterated S-217622 (Ensitrelvir) bound to the main protease (3CLpro/Mpro) of SARS-CoV-2

Summary for 8HEF

• Entry DOI: 10.2210/pdb8hef/pdb
• Descriptor: 3C-like proteinase, 6-[(6-chloranyl-2-methyl-indazol-5-yl)amino]-3-[(1-methyl-1,2,4-triazol-3-yl)methyl]-1-[[2,4,5-tris(fluoranyl)phenyl]methyl]-1,3,5-triazine-2,4-dione, GLYCEROL, ... (4 entities in total)
• Functional Keywords: sars-cov-2, main protease, 3clpro, inhibitor, deuterated compound, viral protein
• Biological source: Severe acute respiratory syndrome coronavirus 2 (2019-nCoV, SARS-CoV-2)
• Total number of polymer chains: 2
• Total formula weight: 67741.78

Authors

Yan, M.,Zhang, H. (deposition date: 2022-11-08, release date: 2023-04-19, Last modification date: 2023-08-30)

Primary citation

Yang, Y.,Cao, L.,Yan, M.,Zhou, J.,Yang, S.,Xu, T.,Huang, S.,Li, K.,Zhou, Q.,Li, G.,Zhu, Y.,Cong, F.,Zhang, H.,Guo, D.,Li, Y.,Zhang, X.
Synthesis of deuterated S-217622 (Ensitrelvir) with antiviral activity against coronaviruses including SARS-CoV-2.
Antiviral Res., 213:105586-105586, 2023

PubMed Abstract: S-217622 (Ensitrelvir) is a reversible severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 3-chymotrypsin-like protease (3CL) inhibitor which obtained emergency regulatory approval in Japan for the treatment of SARS-CoV-2 infection on Nov 22, 2022. Herein, analogs of S-271622 with deuterium-for-hydrogen replacement were synthesized for comparison of the antiviral activities and pharmacokinetic (PK) profiles. Compared to the parent compound, C11-d2-S-217622 compound YY-278 retained in vitro activity against 3CL and SARS-CoV-2. X-ray crystal structural studies showed similar interactions of SARS-CoV-2 3CL with YY-278 and S-271622. The PK profiling revealed the relatively favorable bioavailability and plasma exposure of YY-278. In addition, YY-278, as well as S-217622, displayed broadly anti-coronaviral activities against 6 other coronaviruses that infect humans and animals. These results laid the foundation for further research on the therapeutic potential of YY-278 against COVID-19 and other coronaviral diseases.

PubMed: 36997073
DOI: 10.1016/j.antiviral.2023.105586

Experimental method

X-RAY DIFFRACTION (1.51 Å)