Structural basis for the in vitro efficacy of nirmatrelvir against SARS-CoV-2 variants.
Structural basis for the in vitro efficacy of nirmatrelvir against SARS-CoV-2 variants.
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DOI：
10.1016/j.jbc.2022.101972
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发表时间：
2022-06
影响因子：
4.8
通讯作者：
Steppan, Claire M.
中科院分区：
文献类型：
--
作者：
Greasley, Samantha E.;Noell, Stephen;Plotnikova, Olga;Ferre, RoseAnn;Liu, Wei;Bolanos, Ben;Fennell, Kimberly;Nicki, Jennifer;Craig, Tim;Zhu, Yuao;Stewart, Al E.;Steppan, Claire M.
随着 SARS-CoV-2 变种的不断出现，COVID-19 大流行仍然对公共卫生构成威胁。 Nirmatrelvir (PF-07321332) 是一种可逆共价抑制剂，针对 SARS-CoV-2 的主要蛋白酶 (Mpro)，也是 PAXLOVID（nirmatrelvir 片剂和利托那韦片剂）中的活性蛋白酶抑制剂。然而，nirmatrelvir 针对不断进化的 SARS-CoV-2 变异体的疗效尚不确定。在这里，我们评估了 nirmatrelvir 针对常见变异体 (VOC) 或感兴趣变异体 (VOIs) 的 Mpro 的体外催化活性和效力：Alpha (α, B.1.1.7)、Beta (β, B.1.351)、Delta (δ, B1.617.2)、Gamma (γ, P.1)、Lambda (λ, B.1.1.1.37/C37)、 Omicron (ο, B.1.1.529)，以及原始华盛顿菌株或野生型菌株。这些 VOC/VOIs 在 Mpro 中以不同频率携带普遍突变，特别是 α、β、γ (K90R)、λ (G15S) 和 ο (P132H)。突变体 Mpros 酶动力学的体外生化酶测定表征表明，它们在催化方面与野生型相当。我们发现 nirmatrelvir 对每种突变体 Mpro（包括 P132H）具有相似的效力，在 Omicron 变体中观察到，Ki 为 0.635 nM，而野生型的 Ki 为 0.933 nM。这些观察结果的分子基础是通过溶液相结构动力学和以 1.63 至 2.09 Å 分辨率结合 ο、λ 和 β Mpro 的 nirmatrelvir 的结构测定提供的。这些体外数据表明，PAXLOVID 有潜力将 nirmatrelvir 的血浆浓度维持在比阻止 SARS-CoV-2 VOC/VOI（包括 Omicron）在细胞中复制所需浓度高出许多倍的潜力。
The COVID-19 pandemic continues to be a public health threat with emerging variants of SARS-CoV-2. Nirmatrelvir (PF-07321332) is a reversible, covalent inhibitor targeting the main protease (Mpro) of SARS-CoV-2 and the active protease inhibitor in PAXLOVID (nirmatrelvir tablets and ritonavir tablets). However, the efficacy of nirmatrelvir is underdetermined against evolving SARS-CoV-2 variants. Here, we evaluated the in vitro catalytic activity and potency of nirmatrelvir against the Mpro of prevalent variants of concern (VOCs) or variants of interest (VOIs): Alpha (α, B.1.1.7), Beta (β, B.1.351), Delta (δ, B1.617.2), Gamma (γ, P.1), Lambda (λ, B.1.1.1.37/C37), Omicron (ο, B.1.1.529), as well as the original Washington or wildtype strain. These VOCs/VOIs carry prevalent mutations at varying frequencies in the Mpro specifically for α, β, γ (K90R), λ (G15S), and ο (P132H). In vitro biochemical enzymatic assay characterization of the enzyme kinetics of the mutant Mpros demonstrates that they are catalytically comparable to wildtype. We found that nirmatrelvir has similar potency against each mutant Mpro including P132H that is observed in the Omicron variant with a Ki of 0.635 nM as compared to a Ki of 0.933 nM for wildtype. The molecular basis for these observations were provided by solution-phase structural dynamics and structural determination of nirmatrelvir bound to the ο, λ, and β Mpro at 1.63 to 2.09 Å resolution. These in vitro data suggest that PAXLOVID has the potential to maintain plasma concentrations of nirmatrelvir many-fold times higher than the amount required to stop the SARS-CoV-2 VOC/VOI, including Omicron, from replicating in cells.
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影响因子：
28.3
作者：
Gorbalenya, Alexander E.;Baker, Susan C.;Ziebuhr, John
通讯作者：
Ziebuhr, John
双黄连制剂及活性成分的体外抗SARS-CoV-2活性
影响因子：
8.2
作者：
Su, Hai-xia;Yao, Sheng;Xu, Ye-chun
通讯作者：
Xu, Ye-chun
影响因子：
2.7
作者：
Ullrich S;Ekanayake KB;Otting G;Nitsche C
通讯作者：
Nitsche C
DOI：
10.1208/s12248-020-00532-2
发表时间：
2021-01-05
期刊：
The AAPS journal
影响因子：
--
作者：
Majumder J;Minko T
通讯作者：
Minko T
影响因子：
16.6
作者：
Boras B;Jones RM;Anson BJ;Arenson D;Aschenbrenner L;Bakowski MA;Beutler N;Binder J;Chen E;Eng H;Hammond H;Hammond J;Haupt RE;Hoffman R;Kadar EP;Kania R;Kimoto E;Kirkpatrick MG;Lanyon L;Lendy EK;Lillis JR;Logue J;Luthra SA;Ma C;Mason SW;McGrath ME;Noell S;Obach RS;O' Brien MN;O'Connor R;Ogilvie K;Owen D;Pettersson M;Reese MR;Rogers TF;Rosales R;Rossulek MI;Sathish JG;Shirai N;Steppan C;Ticehurst M;Updyke LW;Weston S;Zhu Y;White KM;García-Sastre A;Wang J;Chatterjee AK;Mesecar AD;Frieman MB;Anderson AS;Allerton C
通讯作者：
Allerton C