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人γ冠状病毒3C/3CL蛋白酶抑制剂设计中的P谷氨酰胺等排体

P Glutamine isosteres in the design of inhibitors of 3C/3CL protease of human viruses of the class.

作者信息

Stubbing Louise A, Hubert Jonathan G, Bell-Tyrer Joseph, Hermant Yann O, Yang Sung Hyun, McSweeney Alice M, McKenzie-Goldsmith Geena M, Ward Vernon K, Furkert Daniel P, Brimble Margaret A

机构信息

School of Chemical Sciences, The University of Auckland 23 Symonds Street and 3b Symonds Street Auckland 1142 New Zealand

Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland 3b Symonds Street Auckland 1142 New Zealand.

出版信息

RSC Chem Biol. 2023 Jun 21;4(8):533-547. doi: 10.1039/d3cb00075c. eCollection 2023 Aug 3.

DOI:10.1039/d3cb00075c
PMID:37547456
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10398354/
Abstract

Viral infections are one of the leading causes of acute morbidity in humans and much endeavour has been made by the synthetic community for the development of drugs to treat associated diseases. Peptide-based enzyme inhibitors, usually short sequences of three or four residues, are one of the classes of compounds currently under development for enhancement of their activity and pharmaceutical properties. This review reports the advances made in the design of inhibitors targeting the family of highly conserved viral proteases 3C/3CL, which play a key role in viral replication and present minimal homology with mammalian proteases. Particular focus is put on the reported development of P glutamine isosteres to generate potent inhibitors mimicking the natural substrate sequence at the site of recognition.'

摘要

病毒感染是人类急性发病的主要原因之一，合成化学领域已付出诸多努力来开发治疗相关疾病的药物。基于肽的酶抑制剂通常由三或四个残基的短序列组成，是目前正在开发以增强其活性和药物性质的一类化合物。本综述报道了针对高度保守的病毒蛋白酶3C/3CL家族设计抑制剂所取得的进展，该家族蛋白酶在病毒复制中起关键作用，且与哺乳动物蛋白酶的同源性极低。特别关注了已报道的P-谷氨酰胺等电子体的开发，以生成在识别位点模拟天然底物序列的强效抑制剂。

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