Alkyne as a Latent Warhead to Covalently Target SARS-CoV-2 Main Protease.
Alkyne as a Latent Warhead to Covalently Target SARS-CoV-2 Main Protease.
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DOI：
10.1021/acs.jmedchem.3c00810
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发表时间：
2023-09-14
影响因子：
7.3
通讯作者：
Zhang, Chao
中科院分区：
文献类型：
--
作者：
Ngo, Chau;Fried, William;Aliyari, Saba;Feng, Joshua;Qin, Chao;Zhang, Shilei;Yang, Hanjing;Shanaa, Jean;Feng, Pinghui;Cheng, Genhong;Chen, Xiaojiang S.;Zhang, Chao
迫切需要改进治疗方法，以更好地控制持续的COVID-19大流行。主要蛋白酶Mpro在SARS-CoV-2复制中起着关键作用，因此代表了抗病毒开发的有吸引力的靶标。我们寻求确定新的亲电子弹头的有效，共价抑制Mpro。通过比较安装在普通支架上的一组弹头对Mpro的效力，我们发现末端炔可以共价修饰Mpro作为潜伏弹头。我们的生化和X-射线结构分析表明，不可逆的形成之间的炔和催化半胱氨酸的Mpro的乙烯基硫键。开发了基于炔抑制剂的可点击探针以测量靶标接合、药物停留时间和脱靶效应。最好的含炔抑制剂在细胞感染模型中有效地抑制SARS-CoV-2感染。我们的研究结果突出了炔作为潜在弹头靶向病毒和其他病毒中的胱氨酸蛋白酶的巨大潜力。
There is an urgent need for improved therapy to better control the ongoing COVID-19 pandemic. The main protease Mpro plays a pivotal role in SARS-CoV-2 replications, thereby representing an attractive target for antiviral development. We seek to identify novel electrophilic warheads for efficient, covalent inhibition of Mpro. By comparing the efficacy of a panel of warheads installed on a common scaffold against Mpro, we discovered that the terminal alkyne could covalently modify Mpro as a latent warhead. Our biochemical and X-ray structural analyses revealed the irreversible formation of the vinyl-sulfide linkage between the alkyne and the catalytic cysteine of Mpro. Clickable probes based on the alkyne inhibitors were developed to measure target engagement, drug residence time, and off-target effects. The best alkyne-containing inhibitors potently inhibited SARS-CoV-2 infection in cell infection models. Our findings highlight great potentials of alkyne as a latent warhead to target cystine proteases in viruses and beyond.
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影响因子：
7.3
作者：
Dragovich, PS;Prins, TJ;Worland, ST
通讯作者：
Worland, ST
影响因子：
18.2
作者：
Devaraj NK
通讯作者：
Devaraj NK
DOI：
10.1056/nejmoa2118542
发表时间：
2022-04-14
期刊：
The New England journal of medicine
影响因子：
--
作者：
Hammond J;Leister-Tebbe H;Gardner A;Abreu P;Bao W;Wisemandle W;Baniecki M;Hendrick VM;Damle B;Simón-Campos A;Pypstra R;Rusnak JM;EPIC-HR Investigators
通讯作者：
EPIC-HR Investigators
影响因子：
4.6
作者：
Chatani, Shunsuke;Nair, Devatha P.;Bowman, Christopher N.
通讯作者：
Bowman, Christopher N.
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。
影响因子：
7.3
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.
通讯作者：
Schofield, Christopher J.