Alkyne Derivatives of SARS-CoV-2 Main Protease Inhibitors Including Nirmatrelvir Inhibit by Reacting Covalently with the Nucleophilic Cysteine.
Alkyne Derivatives of SARS-CoV-2 Main Protease Inhibitors Including Nirmatrelvir Inhibit by Reacting Covalently with the Nucleophilic Cysteine.
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SARS-COV-2主要蛋白酶抑制剂（包括Nirmatrelvir）的碱衍生物通过与亲核性半胱氨酸的共价反应来抑制。
DOI：
10.1021/acs.jmedchem.2c01627
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发表时间：
2023-02-23
影响因子：
7.3
通讯作者：
Schofield, Christopher J.
中科院分区：
文献类型：
--
作者：
Brewitz, Lennart;Dumjahn, Leo;Zhao, Yilin;Owen, C. David;Laidlaw, Stephen M.;Malla, Tika R.;Nguyen, Dung;Lukacik, Petra;Salah, Eidarus;Crawshaw, Adam D.;Warren, Anna J.;Trincao, Jose;Strain-Damerell, Claire;Carroll, Miles W.;Walsh, Martin A.;Schofield, Christopher J.
Nirmatrelvir（PF-07321332）是一种腈类小分子抑制剂，与利托那韦联合用于治疗严重急性呼吸道综合征冠状病毒2（SARS-CoV-2）感染。Nirmatrelvir通过抑制SARS-CoV-2主要蛋白酶（Mpro）中断病毒的生命周期，该蛋白酶是将病毒多聚蛋白加工成功能性非结构蛋白所必需的。我们报告的研究表明，nirmatrelvir和其他Mpro抑制剂的衍生物与非活化的末端炔基定位类似于nirmatrelvir的亲电腈，可以有效地抑制分离的Mpro和SARS-CoV-2在细胞中复制。质谱和晶体学证据表明，炔衍生物抑制Mpro通过与活性位点半胱氨酸（Cys 145）的明显不可逆共价反应，而类似的腈可逆反应。结果突出了Mpro和其他亲核半胱氨酸蛋白酶通过炔的不可逆共价抑制的潜力，与腈相反，炔可以在其末端位置官能化以优化抑制和选择性以及药效学和药代动力学性质。
Nirmatrelvir (PF-07321332) is a nitrile-bearing small-molecule inhibitor that, in combination with ritonavir, is used to treat infections by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Nirmatrelvir interrupts the viral life cycle by inhibiting the SARS-CoV-2 main protease (Mpro), which is essential for processing viral polyproteins into functional nonstructural proteins. We report studies which reveal that derivatives of nirmatrelvir and other Mpro inhibitors with a nonactivated terminal alkyne group positioned similarly to the electrophilic nitrile of nirmatrelvir can efficiently inhibit isolated Mpro and SARS-CoV-2 replication in cells. Mass spectrometric and crystallographic evidence shows that the alkyne derivatives inhibit Mpro by apparent irreversible covalent reactions with the active site cysteine (Cys145), while the analogous nitriles react reversibly. The results highlight the potential for irreversible covalent inhibition of Mpro and other nucleophilic cysteine proteases by alkynes, which, in contrast to nitriles, can be functionalized at their terminal position to optimize inhibition and selectivity, as well as pharmacodynamic and pharmacokinetic properties.
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影响因子：
16.6
作者：
Douangamath A;Fearon D;Gehrtz P;Krojer T;Lukacik P;Owen CD;Resnick E;Strain-Damerell C;Aimon A;Ábrányi-Balogh P;Brandão-Neto J;Carbery A;Davison G;Dias A;Downes TD;Dunnett L;Fairhead M;Firth JD;Jones SP;Keeley A;Keserü GM;Klein HF;Martin MP;Noble MEM;O'Brien P;Powell A;Reddi RN;Skyner R;Snee M;Waring MJ;Wild C;London N;von Delft F;Walsh MA
通讯作者：
Walsh MA
影响因子：
15
作者：
BOTT, G;FIELD, LD;STERNHELL, S
通讯作者：
STERNHELL, S
影响因子：
1.2
作者：
Crawshaw, Adam D.;Beale, Emma, V;Evans, Gwyndaf
通讯作者：
Evans, Gwyndaf
拟肽醛作为肠道病毒和 SARS-CoV-2 广谱抑制剂的设计、合成和生物学评价
影响因子：
7.3
作者：
Dai, Wenhao;Jochmans, Dirk;Liu, Hong
通讯作者：
Liu, Hong
DOI：
10.1073/pnas.2111172118
发表时间：
2021-09-07
影响因子：
11.1
作者：
Chamakuri S;Lu S;Ucisik MN;Bohren KM;Chen YC;Du HC;Faver JC;Jimmidi R;Li F;Li JY;Nyshadham P;Palmer SS;Pollet J;Qin X;Ronca SE;Sankaran B;Sharma KL;Tan Z;Versteeg L;Yu Z;Matzuk MM;Palzkill T;Young DW
通讯作者：
Young DW