8TBE

Co-crystal structure of SARS-CoV-2 Mpro with Pomotrelvir

8TBE の概要

• エントリーDOI: 10.2210/pdb8tbe/pdb
• 分子名称: 3C-like proteinase nsp5, Pomotrelvir bound form (3 entities in total)
• 機能のキーワード: main protease, viral protein, 3cl protease
• 由来する生物種: Severe acute respiratory syndrome coronavirus 2
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 68567.00

構造登録者

Olland, A.,Fontano, E.,White, A. (登録日: 2023-06-28, 公開日: 2023-08-09, 最終更新日: 2023-11-22)

主引用文献

Tong, X.,Keung, W.,Arnold, L.D.,Stevens, L.J.,Pruijssers, A.J.,Kook, S.,Lopatin, U.,Denison, M.,Kwong, A.D.
Evaluation of in vitro antiviral activity of SARS-CoV-2 M pro inhibitor pomotrelvir and cross-resistance to nirmatrelvir resistance substitutions.
Antimicrob.Agents Chemother., 67:e0084023-e0084023, 2023

PubMed Abstract: The unprecedented scale of the COVID-19 pandemic and the rapid evolution of SARS-CoV-2 variants underscore the need for broadly active inhibitors with a high barrier to resistance. The coronavirus main protease (M) is an essential cysteine protease required for viral polyprotein processing and is highly conserved across human coronaviruses. Pomotrelvir is a novel M inhibitor that has recently completed a phase 2 clinical trial. In this report, we demonstrated that pomotrelvir is a potent competitive inhibitor of SARS-CoV-2 M with high selectivity against human proteases. In the enzyme assay, pomotrelvir is also active against M proteins derived from human coronaviruses CoV-229E, CoV-OC43, CoV-HKU1, CoV-NL63, MERS, and SARS-CoV. In cell-based SARS-CoV-2 replicon and SARS-CoV-2 infection assays, pomotrelvir has shown potent inhibitory activity and is broadly active against SARS-CoV-2 clinical isolates including Omicron variants. Many resistance substitutions of the M inhibitor nirmatrelvir confer cross-resistance to pomotrelvir, consistent with the finding from our enzymatic analysis that pomotrelvir and nirmatrelvir compete for the same binding site. In a SARS-CoV-2 infection assay, pomotrelvir is additive when combined with remdesivir or molnupiravir, two nucleoside analogs targeting viral RNA synthesis. In conclusion, our results from the characterization of pomotrelvir antiviral activity support its further clinical development as an alternative COVID-19 therapeutic option.

PubMed: 37800975
DOI: 10.1128/aac.00840-23

実験手法

X-RAY DIFFRACTION (2.15 Å)