Inhibition mechanism of SARS-CoV-2 main protease by ebselen and its derivatives.
Inhibition mechanism of SARS-CoV-2 main protease by ebselen and its derivatives.
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DOI：
10.1038/s41467-021-23313-7
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发表时间：
2021-05-24
影响因子：
16.6
通讯作者：
Samar Hasnain S
中科院分区：
文献类型：
--
作者：
Amporndanai K;Meng X;Shang W;Jin Z;Rogers M;Zhao Y;Rao Z;Liu ZJ;Yang H;Zhang L;O'Neill PM;Samar Hasnain S
SARS-CoV-2大流行引发了全球开发治疗方法的努力。SARS-CoV-2的主要蛋白酶（Mpro）对病毒复制至关重要，是治疗开发的关键靶点。一种名为依布硒啉的有机硒药物已被证明具有有效的Mpro抑制和抗病毒活性。我们已经研究了结合方式的依布硒啉及其衍生物在Mpro通过高分辨率共结晶和研究其化学反应性通过质谱。对于许多衍生物，观察到比依布硒啉更强的Mpro抑制和拯救感染细胞的有效能力。在Mpro与依布硒啉和MR 6 -31-2的晶体学结构中发现了与催化二联体的半胱氨酸结合的游离硒原子，表明酶结合的有机硒共价加合物水解并形成酚类副产物，这一点通过质谱法得到证实。靶点与硒化抑制机制的结合表明这些化合物对SARS-CoV-2和其他人畜共患β-冠状病毒具有更广泛的治疗应用。Ebselen是一种有机硒药物，可抑制SARS-CoV-2主要蛋白酶（Mpro）。在这里，作者将Mpro与依布硒啉和依布硒啉衍生物共结晶，并在晶体结构中观察到酶结合的有机硒共价加合物，这也通过质谱分析证实。
The SARS-CoV-2 pandemic has triggered global efforts to develop therapeutics. The main protease of SARS-CoV-2 (Mpro), critical for viral replication, is a key target for therapeutic development. An organoselenium drug called ebselen has been demonstrated to have potent Mpro inhibition and antiviral activity. We have examined the binding modes of ebselen and its derivative in Mpro via high resolution co-crystallography and investigated their chemical reactivity via mass spectrometry. Stronger Mpro inhibition than ebselen and potent ability to rescue infected cells were observed for a number of derivatives. A free selenium atom bound with cysteine of catalytic dyad has been revealed in crystallographic structures of Mpro with ebselen and MR6-31-2 suggesting hydrolysis of the enzyme bound organoselenium covalent adduct and formation of a phenolic by-product, confirmed by mass spectrometry. The target engagement with selenation mechanism of inhibition suggests wider therapeutic applications of these compounds against SARS-CoV-2 and other zoonotic beta-corona viruses. Ebselen is an organoselenium drug that inhibits the SARS-CoV-2 main protease (Mpro). Here, the authors co-crystallised Mpro with ebselen and an ebselen derivative and observed an enzyme bound organoselenium covalent adduct in the crystal structures, which was also confirmed by mass spectrometry analysis.
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影响因子：
16.8
作者：
Jin, Zhenming;Zhao, Yao;Rao, Zihe
通讯作者：
Rao, Zihe
DOI：
10.1107/s090744491003982x
发表时间：
2011-04
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Evans PR
通讯作者：
Evans PR
影响因子：
64.8
作者：
Plante JA;Liu Y;Liu J;Xia H;Johnson BA;Lokugamage KG;Zhang X;Muruato AE;Zou J;Fontes-Garfias CR;Mirchandani D;Scharton D;Bilello JP;Ku Z;An Z;Kalveram B;Freiberg AN;Menachery VD;Xie X;Plante KS;Weaver SC;Shi PY
通讯作者：
Shi PY
影响因子：
3.4
作者：
Sharpley AL;Williams C;Holder AA;Godlewska BR;Singh N;Shanyinde M;MacDonald O;Cowen PJ
通讯作者：
Cowen PJ
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