新型冠状病毒主蛋白酶及其抑制剂研究进展

Main Protease of SARS-CoV-2 and Its Inhibitors: Research Advances

新型冠状病毒肺炎(COVID-19)是由新型冠状病毒(SARS-CoV-2)引起的传染性疾病,而主蛋白酶具有高度的序列保守性,在冠状病毒生命周期中起关键作用,是理想的抗病毒药物设计靶标。本文概述了SARS-CoV-2主蛋白酶的结构和催化反应机制,并根据主蛋白酶抑制剂结构和机制的不同,将已报道的抑制剂分为肽模拟抑制剂和非肽类小分子抑制剂两类,其中以Paxlovid为代表的肽模拟抑制剂,根据其基团可分为基于金属络合物类的Ebselen,基于亚硫酸氢盐类的GC376与GC373,基于醛类的钙蛋白酶抑制剂Ⅱ、Ⅻ和α酮酰胺类的化合物13a、13b。此外,非肽类小分子药物黄芩素也极具潜力。最后对主蛋白酶抑制剂的抗病毒活性、耐药性、稳定性和广谱性等进展进行综述,为广谱抗病毒药物的研发提供参考。

The COVID-19 pandemic caused by SARS-CoV-2 has posed a serious threat to human health.Main protease,which plays an essential role in the life cycle of coronaviruses and belongs toβcoronavirus genus,is an appealing target for the development of inhibitors with its genus-based high conservation.In this review,the structure and catalytic reaction mechanism of main protease are summarized.The reported inhibitors are divided into peptide-mimetic inhibitors and non-peptide small molecular inhibitors.The former,represented by Paxlovid,can be divided into Ebselen based on metal complexes,GC376 and GC373 based on sulfurous acid,and calpain inhibitorsⅡ,ⅦandαKetonamide compounds 13a,13b.Baicalein,a non-peptide small molecular inhibitor,also has great potential.Additionally,this paper reviews the recent research progress in antiviral activity,resistance,stability,and broad-spectrum properties of related inhibitors in order to provide reference for developing broad-spectrum anti-coronavirus drugs.