A Systematic Survey of Reversibly Covalent Dipeptidyl Inhibitors of the SARS-CoV-2 Main Protease.
A Systematic Survey of Reversibly Covalent Dipeptidyl Inhibitors of the SARS-CoV-2 Main Protease.
复制标题
SARS-CoV-2 主要蛋白酶的可逆共价二肽基抑制剂的系统调查。
DOI：
10.1021/acs.jmedchem.3c00221
复制
发表时间：
2023
影响因子：
7.3
通讯作者：
Allen,Robe
中科院分区：
文献类型：
--
作者：
Geng,ZhiZachary;Atla,Sandeep;Shaabani,Namir;Vulupala,Veerabhadra;Yang,KaiS;Alugubelli,YugendarR;Khatua,Kaustav;Chen,Peng-Hsun;Xiao,Jing;Blankenship,LaurenR;Ma,XinyuR;Vatansever,ErolC;Cho,Chia-ChuanD;Ma,Yuying;Allen,Robe
SARS-CoV-2是COVID-19病原体，其复制和致病依赖于其主要蛋白酶（MPro）。MPro是开发SARS-CoV-2抗病毒药物的一个已证实的靶点。过去的研究已经系统地探索了三肽基抑制剂，如nirmatrelvir作为MPro抑制剂。然而，二肽基抑制剂，特别是那些在其P2位上具有螺环残基的二肽基抑制剂尚未被系统地研究。本工作合成了约30个二肽基MPro抑制剂，并对其酶抑制活性、与MPro复合物的结构、细胞MPro抑制活性、抗病毒活性、细胞毒性和体外代谢稳定性进行了表征。我们的结果表明，MPro具有灵活的S2口袋，可以容纳具有较大P2残基的抑制剂，并表明具有较大P2螺环残基的二肽基抑制剂，例如（S）-2-氮杂螺[4，4]壬烷-3-羧酸酯和（S）-2-氮杂螺[4，5]癸烷-3-羧酸酯具有有利的特征。其中一个化合物MPI 60含有一个P2（S）-2-氮杂螺[4，4]壬烷-3-羧酸酯，显示出高的抗病毒效力、低的细胞毒性和高的体外代谢稳定性。
SARS-CoV-2, the COVID-19 pathogen, relies on its main protease (MPro) for replication and pathogenesis. MProis a demonstrated target for the development of antivirals for SARS-CoV-2. Past studies have systematically explored tripeptidyl inhibitors such as nirmatrelvir as MProinhibitors. However, dipeptidyl inhibitors especially those with a spiro residue at their P2 position have not been systematically investigated. In this work, we synthesized about 30 dipeptidyl MProinhibitors and characterized them on enzymatic inhibition potency, structures of their complexes with MPro, cellular MProinhibition potency, antiviral potency, cytotoxicity, andin vitrometabolic stability. Our results indicated that MProhas a flexible S2 pocket to accommodate inhibitors with a large P2 residue and revealed that dipeptidyl inhibitors with a large P2 spiro residue such as (S)-2-azaspiro [4,4]nonane-3-carboxylate and (S)-2-azaspiro[4,5]decane-3-carboxylate have favorable characteristics. One compound, MPI60, containing a P2 (S)-2-azaspiro[4,4]nonane-3-carboxylate displayed high antiviral potency, low cellular cytotoxicity, and highin vitrometabolic stability.