Mutations in spike protein and allele variations in ACE2 impact targeted therapy strategies against SARS-CoV-2

查看全文 作　　者：Chuan-Jun [1,2,3]Shu;Xuan [4]Huang;Hui-Hao [2]Tang;Ding-Ding [5]Mo;Jian-Wei [1]Zhou;Cheng [2]Deng

机构地区：[1]Department of Molecular Cell Biology&Toxicology,Center for Global Health,School of Public Health,Nanjing Medical University,Nanjing,Jiangsu 211166,China;[2]Jiangsu Key Laboratory for Biodiversity and Biotechnology,College of Life Sciences,Nanjing Normal University,Nanjing,Jiangsu 210023,China;[3]Department of Bioinformatics,School of Biomedical Engineering and Informatics,Nanjing Medical University,Nanjing,Jiangsu 211166,China;[4]Reproductive Medical Center,Jinling Hospital Affiliated to Medical School of Nanjing University,Nanjing,Jiangsu 210002,China;[5]School of Chemical Biology and Biotechnology,Peking University Shenzhen Graduate School,Shenzhen,Guangdong 518055,China

出　　处：《Zoological Research》索引2021年第42卷第2期,共12页

基　　金：supported by the National Key Research and Development Program of China (2018YFD0900602);National Natural Science Foundation of China (31970388, 31701234);Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD);Natural Science Foundation of the Jiangsu Higher Education Institutions (17KJB180006);Natural Science Foundation from Jiangsu Province (BK20160043, BK20151546, 15KJA180004and BK20171035);Jiangsu Distinguished Professor Funding。 摘　　要：Coronavirus disease 2019(COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2(SARS-Co V-2), has spread rapidly worldwide with high rates of transmission and substantial mortality. To date, however, no effective treatments or enough vaccines for COVID-19 are available. The roles of angiotensin converting enzyme 2(ACE2) and spike protein in the treatment of COVID-19 are major areas of research. In this study, we explored the potential of ACE2 and spike protein as targets for the development of antiviral agents against SARS-Co V-2. We analyzed clinical data, genetic data, and receptor binding capability.Clinical data revealed that COVID-19 patients with comorbidities related to an abnormal reninangiotensin system exhibited more early symptoms and poorer prognoses. However, the relationship between ACE2 expression and COVID-19progression is still not clear. Furthermore, if ACE2 is not a good targetable protein, it would not be applicable across a wide range of populations. The spike-S1 receptor-binding domain that interacts with ACE2 showed various amino acid mutations based on sequence analysis. We identified two spike-S1 point mutations(V354 F and V470 A) by receptorligand docking and binding enzyme-linked immunosorbent assays. These variants enhanced the binding of the spike protein to ACE2 receptors and were potentially associated with increased infectivity. Importantly, the number of patients infected with the V354 F and V470 A mutants has increased with the development of the SARS-Co V-2 pandemic. These results suggest that ACE2 and spike-S1 are likely not ideal targets for the design of peptide drugs to treat COVID-19 in different populations. 关键词：SARS-CoV-2 COVID-19 ACE2 Spike protein Receptor-ligand docking Drug therapy

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Mutations in spike protein and allele variations in ACE2 impact targeted therapy strategies against SARS-CoV-2

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