SARS-CoV-2突变背景下的病毒入侵机制研究进展与干预策略 (2022)

<p indent="0mm">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-CoV, 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.1.1.529). The Omicron variant is currently in circulation. The entry-related characteristics of VOCs may indicate global epidemiological trends and shed light on future pandemic dynamics. The entry mechanism of SARS-CoV-2, the first and crucial step in the establishment of a viral infection, has been extensively studied over the past two years. As the molecular mechanisms involved in entry are gradually being elucidated, interventions in key events may prevent viral entry and provide information for drug development and clinical treatment. Because the cellular entry mechanism of coronaviruses is relatively conserved, the first step in interrupting viral infection—blocking the entry process—is a promising target for the development of new preventive and therapeutic drugs against COVID-19 and even pan-coronavirus inhibitors, including small molecules, peptides, and monoclonal antibodies. Researchers have identified potential drug targets involved in the SARS-CoV-2 entry process, such as spike proteins, ACE2, and host proteases. Inhibition of the viral entry process is expected to reduce viral load in patients, thereby alleviating symptoms and improving prognosis. Recently, computer-aided drug design has emerged as a powerful and productive tool for drug discovery, in addition to experimental methods in the wet lab. In future anti-SARS-CoV-2 drug discovery, the flexible combination and optimized design of drug discovery strategies to improve the efficiency of drug development will be the trend. In this review, we outline the mechanism of SARS-CoV-2 entry into cells, describe the entry properties of VOCs currently defined by the WHO, and present the progress in the discovery of SARS-CoV-2 entry inhibitors.