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Mutations in spike protein and allele variations in ACE2 impact targeted therapy strategies against SARS-CoV-2.
Zool Res. 2021 Mar 18; 42(2):170-181.ZR

Abstract

Coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-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-CoV-2. We analyzed clinical data, genetic data, and receptor binding capability. Clinical data revealed that COVID-19 patients with comorbidities related to an abnormal renin-angiotensin system exhibited more early symptoms and poorer prognoses. However, the relationship between ACE2 expression and COVID-19 progression 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 (V354F and V470A) by receptor-ligand 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 V354F and V470A mutants has increased with the development of the SARS-CoV-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.

Authors+Show Affiliations

Department of Molecular Cell Biology & Toxicology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu 211166, China. Jiangsu Key Laboratory for Biodiversity and Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing, Jiangsu 210023, China. Department of Bioinformatics, School of Biomedical Engineering and Informatics, Nanjing Medical University, Nanjing, Jiangsu 211166, China.Reproductive Medical Center, Jinling Hospital Affiliated to Medical School of Nanjing University, Nanjing, Jiangsu 210002, China.Jiangsu Key Laboratory for Biodiversity and Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing, Jiangsu 210023, China.School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, Guangdong 518055, China.Department of Molecular Cell Biology & Toxicology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu 211166, China. E-mail: jwzhou@njmu.edu.cn.Jiangsu Key Laboratory for Biodiversity and Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing, Jiangsu 210023, China. E-mail:dengcheng@njnu.edu.cn.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

33738989

Citation

Shu, Chuan-Jun, et al. "Mutations in Spike Protein and Allele Variations in ACE2 Impact Targeted Therapy Strategies Against SARS-CoV-2." Zoological Research, vol. 42, no. 2, 2021, pp. 170-181.
Shu CJ, Huang X, Tang HH, et al. Mutations in spike protein and allele variations in ACE2 impact targeted therapy strategies against SARS-CoV-2. Zool Res. 2021;42(2):170-181.
Shu, C. J., Huang, X., Tang, H. H., Mo, D. D., Zhou, J. W., & Deng, C. (2021). Mutations in spike protein and allele variations in ACE2 impact targeted therapy strategies against SARS-CoV-2. Zoological Research, 42(2), 170-181. https://doi.org/10.24272/j.issn.2095-8137.2020.301
Shu CJ, et al. Mutations in Spike Protein and Allele Variations in ACE2 Impact Targeted Therapy Strategies Against SARS-CoV-2. Zool Res. 2021 Mar 18;42(2):170-181. PubMed PMID: 33738989.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Mutations in spike protein and allele variations in ACE2 impact targeted therapy strategies against SARS-CoV-2. AU - Shu,Chuan-Jun, AU - Huang,Xuan, AU - Tang,Hui-Hao, AU - Mo,Ding-Ding, AU - Zhou,Jian-Wei, AU - Deng,Cheng, PY - 2021/3/19/entrez PY - 2021/3/20/pubmed PY - 2021/3/26/medline KW - ACE2 KW - COVID-19 KW - Drug therapy KW - Receptor-ligand docking KW - SARS-CoV-2 KW - Spike protein SP - 170 EP - 181 JF - Zoological research JO - Zool Res VL - 42 IS - 2 N2 - Coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-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-CoV-2. We analyzed clinical data, genetic data, and receptor binding capability. Clinical data revealed that COVID-19 patients with comorbidities related to an abnormal renin-angiotensin system exhibited more early symptoms and poorer prognoses. However, the relationship between ACE2 expression and COVID-19 progression 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 (V354F and V470A) by receptor-ligand 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 V354F and V470A mutants has increased with the development of the SARS-CoV-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. SN - 2095-8137 UR - https://www.unboundmedicine.com/medline/citation/33738989/Mutations_in_spike_protein_and_allele_variations_in_ACE2_impact_targeted_therapy_strategies_against_SARS_CoV_2_ L2 - http://www.zoores.ac.cn/EN/10.24272/j.issn.2095-8137.2020.301 DB - PRIME DP - Unbound Medicine ER -