9AUL

Structure of SARS-CoV-2 Mpro mutant (A173V,T304I)) in complex with Nirmatrelvir (PF-07321332)

9AUL の概要

• エントリーDOI: 10.2210/pdb9aul/pdb
• 分子名称: 3C-like proteinase nsp5, (1R,2S,5S)-N-{(1E,2S)-1-imino-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl}-6,6-dimethyl-3-[3-methyl-N-(trifluoroacetyl)-L-valyl]-3-azabicyclo[3.1.0]hexane-2-carboxamide (3 entities in total)
• 機能のキーワード: protease, sars-cov, viral protein, hydrolase-inhibitor complex, hydrolase/inhibitor
• 由来する生物種: Severe acute respiratory syndrome coronavirus 2 (2019-nCoV, SARS-CoV-2)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 34367.19

構造登録者

Gajiwala, K.S.,Greasley, S.E.,Ferre, R.A.,Liu, W.,Stewart, A.E. (登録日: 2024-02-29, 公開日: 2024-08-07, 最終更新日: 2024-10-23)

主引用文献

Zhu, Y.,Yurgelonis, I.,Noell, S.,Yang, Q.,Guan, S.,Li, Z.,Hao, L.,Rothan, H.,Rai, D.K.,McMonagle, P.,Baniecki, M.L.,Greasley, S.E.,Plotnikova, O.,Lee, J.,Nicki, J.A.,Ferre, R.,Byrnes, L.J.,Liu, W.,Craig, T.K.,Steppan, C.M.,Liberator, P.,Soares, H.D.,Allerton, C.M.N.,Anderson, A.S.,Cardin, R.D.
In vitro selection and analysis of SARS-CoV-2 nirmatrelvir resistance mutations contributing to clinical virus resistance surveillance.
Sci Adv, 10:eadl4013-eadl4013, 2024

PubMed Abstract: To facilitate the detection and management of potential clinical antiviral resistance, in vitro selection of drug-resistant severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) against the virus M inhibitor nirmatrelvir (Paxlovid active component) was conducted. Six M mutation patterns containing T304I alone or in combination with T21I, L50F, T135I, S144A, or A173V emerged, with A173V+T304I and T21I+S144A+T304I mutations showing >20-fold resistance each. Biochemical analyses indicated inhibition constant shifts aligned to antiviral results, with S144A and A173V each markedly reducing nirmatrelvir inhibition and M activity. SARS-CoV-2 surveillance revealed that in vitro resistance-associated mutations from our studies and those reported in the literature were rarely detected in the Global Initiative on Sharing All Influenza Data database. In the Paxlovid Evaluation of Protease Inhibition for COVID-19 in High-Risk Patients trial, E166V was the only emergent resistance mutation, observed in three Paxlovid-treated patients, none of whom experienced COVID-19-related hospitalization or death.

PubMed: 39047088
DOI: 10.1126/sciadv.adl4013

実験手法

X-RAY DIFFRACTION (2.421 Å)