Structure and inhibition of the SARS-CoV-2 main protease reveal strategy for developing dual inhibitors against M(pro) and cathepsin L.
Structure and inhibition of the SARS-CoV-2 main protease reveal strategy for developing dual inhibitors against M(pro) and cathepsin L.
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DOI：
10.1126/sciadv.abe0751
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发表时间：
2020-12
期刊：
影响因子：
13.6
通讯作者：
Wang J
中科院分区：
文献类型：
--
作者：
Sacco MD;Ma C;Lagarias P;Gao A;Townsend JA;Meng X;Dube P;Zhang X;Hu Y;Kitamura N;Hurst B;Tarbet B;Marty MT;Kolocouris A;Xiang Y;Chen Y;Wang J
具有双抑制剂的SARS-CoV-2 Mpro的x射线晶体结构为新冠病毒抗病毒药物的设计提供了新的方向。SARS-CoV-2的主蛋白酶（Mpro）是抗病毒药物的关键靶点。虽然大多数Mpro抑制剂在P1位点有一个γ-内酰胺谷氨酰胺替代物，但我们最近发现一些Mpro抑制剂在P1位点有疏水部分，包括钙蛋白酶抑制剂II和XII，它们也对人组织蛋白酶L（一种对病毒进入很重要的宿主蛋白酶）有活性。在这项研究中，我们求解了Mpro与calpain抑制剂II和XII以及三种GC-376类似物配合物的x射线晶体结构。Mpro与calpain inhibitor II的结构证实了S1口袋可以容纳疏水蛋氨酸侧链，挑战了在该位置需要亲水性残基的想法。钙蛋白酶抑制剂XII的结构显示出意想不到的倒置结合姿态。总之，本文提出的生化、计算、结构和细胞数据为开发双重抑制剂作为SARS-CoV-2抗病毒药物提供了新的方向。
X-ray crystal structures of SARS-CoV-2 Mpro with dual inhibitors provide a new direction for the designing of COVID-19 antivirals. The main protease (Mpro) of SARS-CoV-2 is a key antiviral drug target. While most Mpro inhibitors have a γ-lactam glutamine surrogate at the P1 position, we recently found that several Mpro inhibitors have hydrophobic moieties at the P1 site, including calpain inhibitors II and XII, which are also active against human cathepsin L, a host protease that is important for viral entry. In this study, we solved x-ray crystal structures of Mpro in complex with calpain inhibitors II and XII and three analogs of GC-376. The structure of Mpro with calpain inhibitor II confirmed that the S1 pocket can accommodate a hydrophobic methionine side chain, challenging the idea that a hydrophilic residue is necessary at this position. The structure of calpain inhibitor XII revealed an unexpected, inverted binding pose. Together, the biochemical, computational, structural, and cellular data presented herein provide new directions for the development of dual inhibitors as SARS-CoV-2 antivirals.
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影响因子：
6.7
作者：
Galasiti Kankanamalage AC;Kim Y;Damalanka VC;Rathnayake AD;Fehr AR;Mehzabeen N;Battaile KP;Lovell S;Lushington GH;Perlman S;Chang KO;Groutas WC
通讯作者：
Groutas WC
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
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通讯作者：
Cowtan, K
影响因子：
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作者：
Chou, CY;Chang, HC;Chang, GG
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影响因子：
15
作者：
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Hong, Mei
影响因子：
4.4
作者：
FELLER, SE;ZHANG, YH;BROOKS, BR
通讯作者：
BROOKS, BR