SARS-CoV-2突变背景下的病毒入侵机制研究进展与干预策略  

Research progress and intervention strategies against SARS-CoV-2 viral entry

作　　者：王革[1] 白宇昊 王泽轩 徐颖洁 Ge Wang;Yuhao Bai;Zexuan Wang;Yingjie Xu(College of Stomatologr,Shanghai Jiao Tong Universiy,Shanghai 200120.China;Department of Biochemisry and Molecular and Cellular Biolog,Shanghai Jiao Tong University School of Medicine,Shanghai 200025,China;Shanghai Key Laboratory for Tumor Microenironment and Inflamwudion.Shanghai 200025,China)

机构地区：[1]上海交通大学口腔医学院,上海200120 [2]上海交通大学医学院生物化学与分子细胞生物学系,上海200025 [3]上海市肿瘤微环境与炎症重点实验室,上海200025

出　　处：《科学通报》2022年第28期3386-3410,共25页Chinese Science Bulletin

基　　金：上海交通大学-以色列希伯来大学联合基金新冠研究种子基金;国家重点研发计划(2021YFA1301400);上海交通大学医学院第15期大学生创新训练计划(202210248291)资助。

摘　　要：自2019冠状病毒病(coronavirus disease 2019, COVID-19)被报道以来,其病原体重症急性呼吸综合征冠状病毒2(severe acute respiratory syndrome coronavirus 2, SARS-CoV-2)已在世界范围内大流行超过2年,目前仍有持续流行的趋势. SARS-CoV-2入侵细胞的过程由其包膜上刺突糖蛋白(spike glycoprotein)结合人类血管紧张素转化酶2(human angiotensin converting enzyme 2, hACE2)受体后介导病毒-细胞间的膜融合来实现.在过去的2年内,大量的研究聚焦于SARS-CoV-2入侵细胞这一病毒感染的关键步骤上,有望通过阐明入侵相关分子机制,针对其中关键事件进行干预从而抑制病毒入侵,为药物设计和临床治疗提供依据.然而在COVID-19持续流行期间,不断有新的SARS-CoV-2突变株产生.入侵特性的差异常表现为传播性、致病力等方面的改变,对基础研究和疫情防控提出了巨大挑战.本文在概述SARS-CoV-2入侵分子机制主要研究进展的基础上,对几种主流突变株的入侵特点进行总结,并介绍干预SARS-CoV-2入侵的潜在药物靶点.Since coronavirus disease 2019(COVID-19) was reported in late 2019, its causative agent, the severe acute respiratory syndrome coronavirus 2(SARS-CoV-2), has been spreading worldwide for more than two years, and the trend continues unabated. SARS-CoV-2 is a single positive-stranded RNA virus from the same β-coronavirus family as SARS-Co V, which caused a severe acute respiratory syndrome(SARS) epidemic in 2003. Entry into the cell is mediated by the binding of the spike glycoprotein on the envelope to angiotensin converting enzyme 2(ACE2) on the host cell, possibly with the help of co-receptors, adhesion factors, or alternative receptors. During the process of virus assembly, release, cell adhesion, and entry into the host cell, the SARS-CoV-2 spike protein must undergo a series of structural changes, including cleavage and conformational changes, to achieve membrane fusion function. After binding to cell surface receptors, SARS-CoV-2 has two invasion pathways:(i) The direct fusion pathway at the cell membrane interface, and(ii) the clathrin-mediated endocytosis pathway. In both cases, the SARS-CoV-2 spike protein must be cleaved by furin-like proteins at the S1/S2 site.Host proteases, mainly TMPRSS-2 or cathepsin, are involved in cleavage at the S2′ site, corresponding to pathway(i) or(ii). The entire entry process ends when the viral genome enters the cytosol.During the replication cycle of SARS-CoV-2, genomic RNA can be mutated. Accumulation of mutations, particularly in the spike protein, may result in new variants that differ in infectivity, transmissibility, virulence, and/or immune escape capability. These changes can alter the prevailing lineage in circulation, trigger a new wave of public health events, and threaten scientific research, clinical prevention, and treatment. The World Health Organization(WHO) has identified five mutant strains as variants of concern(VOCs) by assessing their public health significance worldwide: Alpha(B.1.1.7),Beta(B.1.351), Gamma(P.1), Delta(B.1.617.2), and Omicron(B.1.1

关 键 词：SARS-CoV-2 刺突糖蛋白 病毒入侵 新冠突变 病毒入侵抑制剂 

分 类 号：R563.1[医药卫生—呼吸系统]