Volume 42 Issue 2
Mar.  2021
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Chuan-Jun Shu, Xuan Huang, Hui-Hao Tang, Ding-Ding Mo, Jian-Wei Zhou, Cheng Deng. Mutations in spike protein and allele variations in ACE2 impact targeted therapy strategies against SARS-CoV-2. Zoological Research, 2021, 42(2): 170-181. doi: 10.24272/j.issn.2095-8137.2020.301
Citation: Chuan-Jun Shu, Xuan Huang, Hui-Hao Tang, Ding-Ding Mo, Jian-Wei Zhou, Cheng Deng. Mutations in spike protein and allele variations in ACE2 impact targeted therapy strategies against SARS-CoV-2. Zoological Research, 2021, 42(2): 170-181. doi: 10.24272/j.issn.2095-8137.2020.301

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

doi: 10.24272/j.issn.2095-8137.2020.301
#Authors contributed equally to this work
Funds:  This work was 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, 15KJA180004 and BK20171035), and Jiangsu Distinguished Professor Funding
More Information
  • 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 contributed equally to this work
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  • [1]
    Beigel JH, Tomashek KM, Dodd LE, Mehta AK, Zingman BS, Kalil AC, et al. 2020. Remdesivir for the treatment of Covid-19-preliminary report. New England Journal of Medicine, 383(10): 992−994. doi: 10.1056/NEJMc2022236
    Boas LCPV, Campos ML, Berlanda RLA, De Carvalho Neves N, Franco OL. 2019. Antiviral peptides as promising therapeutic drugs. Cellular and Molecular Life Sciences, 76(18): 3525−3542. doi: 10.1007/s00018-019-03138-w
    Cao YN, Li L, Feng ZM, Wan SQ, Huang PD, Sun XH, et al. 2020a. Comparative genetic analysis of the novel coronavirus (2019-nCoV/SARS-CoV-2) receptor ACE2 in different populations. Cell Discovery, 6(1): 11. doi: 10.1038/s41421-020-0147-1
    Cao YN, Li L, Xu M, Feng ZM, Sun XH, Lu JL, et al. 2020b. The ChinaMAP analytics of deep whole genome sequences in 10, 588 individuals. Cell Research, 30(9): 717−731. doi: 10.1038/s41422-020-0322-9
    Chen C, Zhang Y, Huang JY, Yin P, Cheng ZS, Wu JY, et al. 2020. Favipiravir versus Arbidol for COVID-19: a randomized clinical trial. medRxiv. doi: 10.1101/2020.03.17.20037432.
    Fang L, Karakiulakis G, Roth M. 2020. Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection?. The Lancet Respiratory Medicine, 8(4): e21. doi: 10.1016/S2213-2600(20)30116-8
    Gao Q, Bao LL, Mao HY, Wang L, Xu KW, Yang MN, et al. 2020. Development of an inactivated vaccine candidate for SARS-CoV-2. Science, 369(6499): 77−81. doi: 10.1126/science.abc1932
    Gao YD, Huang JF. 2011. An extension strategy of discovery studio 2.0 for non-bonded interaction energy automatic calculation at the residue level. Zoological Research, 32(3): 262−266.
    Garg VK, Avashthi H, Tiwari A. 2016. MFPPI–Multi FASTA ProtParam interface. Bioinformation, 12(2): 74−77. doi: 10.6026/97320630012074
    Geleris J, Sun Y, Platt J, Zucker J, Baldwin MR, Hripcsak G, et al. 2020. Observational Study of Hydroxychloroquine in Hospitalized Patients with Covid-19. New England Journal of Medicine, 382(25): 2411−2418. doi: 10.1056/NEJMoa2012410
    Gu HJ, Xie ZD, Li TL, Zhang SG, Lai CC, Zhu P, et al. 2016. Angiotensin-converting enzyme 2 inhibits lung injury induced by respiratory syncytial virus. Scientific Reports, 6(1): 19840. doi: 10.1038/srep19840
    Hamzelou J. 2020. Does a cell protein explain covid-19 severity?. New Scientist, 246(3277): 9. doi: 10.1016/S0262-4079(20)30705-3
    Holshue ML, Debolt C, Lindquist S, Lofy KH, Wiesman J, Bruce H, et al. 2020. First Case of 2019 Novel Coronavirus in the United States. New England Journal of Medicine, 382(10): 929−936. doi: 10.1056/NEJMoa2001191
    Huang CL, Wang YM, Li XW, Ren LL, Zhao JP, Hu Y, et al. 2020a. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. The Lancet, 395(10223): 497−506. doi: 10.1016/S0140-6736(20)30183-5
    Huang MX, Li M, Xiao F, Pang PF, Liang JB, Tang TT, et al. 2020b. Preliminary evidence from a multicenter prospective observational study of the safety and efficacy of chloroquine for the treatment of COVID-19. National Science Review, 7(9): 1428−1436. doi: 10.1093/nsr/nwaa113
    Imai Y, Kuba K, Penninger JM. 2007. Angiotensin-converting enzyme 2 in acute respiratory distress syndrome. Cellular and Molecular Life Sciences, 64(15): 2006−2012. doi: 10.1007/s00018-007-6228-6
    Lek M, Karczewski KJ, Minikel EV, Samocha KE, Banks E, Fennell T, et al. 2016. Analysis of protein-coding genetic variation in 60,706 humans. Nature, 536(7616): 285−291. doi: 10.1038/nature19057
    Lewis PO, Kumar S, Tamura K, Nei M. 1995. MEGA: Molecular evolutionary genetics analysis, version 1.02. Systematic Biology, 44(4): 576−577.
    Li L, Zhang W, Hu Y, Tong XL, Zheng SG, Yang JT, et al. 2020a. Effect of convalescent plasma therapy on time to clinical improvement in patients with severe and life-threatening COVID-19: a randomized clinical trial. JAMA, 324(5): 460−470. doi: 10.1001/jama.2020.10044
    Li QQ, Wu JJ, Nie JH, Zhang L, Hao H, Liu S, et al. 2020b. The impact of mutations in SARS-CoV-2 spike on viral infectivity and antigenicity. Cell, 182(5): 1284−1294. doi: 10.1016/j.cell.2020.07.012
    Li XC, Zhang J, Zhuo JL. 2017. The vasoprotective axes of the renin-angiotensin system: Physiological relevance and therapeutic implications in cardiovascular, hypertensive and kidney diseases. Pharmacological Research, 125: 21−38. doi: 10.1016/j.phrs.2017.06.005
    Mirochnik Y, Aurora A, Schulze-Hoepfner FT, Deabes A, Shifrin V, Beckmann R, et al. 2009. Short pigment epithelial-derived factor-derived peptide inhibits angiogenesis and tumor growth. Clinical Cancer Research, 15(5): 1655−1663. doi: 10.1158/1078-0432.CCR-08-2113
    Ordog R. 2008. PyDeT, a PyMOL plug-in for visualizing geometric concepts around proteins. Bioinformation, 2(8): 346−347. doi: 10.6026/97320630002346
    Rohl CA, Strauss CEM, Misura KMS, Baker D. 2004. Protein structure prediction using Rosetta. Methods in Enzymology, 383: 66−93.
    Rozas J, Ferrer-Mata A, Sánchez-DelBarrio JC, Guirao-Rico S, Librado P, Ramos-Onsins SE, et al. 2017. DnaSP 6: DNA sequence polymorphism analysis of large data sets. Molecular Biology and Evolution, 34(12): 3299−3302. doi: 10.1093/molbev/msx248
    Shen CG, Wang ZQ, Zhao F, Yang Y, Li JX, Yuan J, et al. 2020. Treatment of 5 critically Ill patients with COVID-19 with convalescent plasma. JAMA, 323(16): 1582−1589. doi: 10.1001/jama.2020.4783
    Shi JZ, Wen ZY, Zhong GX, Yang HL, Wang C, Huang BY, et al. 2020a. Susceptibility of ferrets, cats, dogs, and other domesticated animals to SARS-coronavirus 2. Science, 368(6494): 1016−1020. doi: 10.1126/science.abb7015
    Shi R, Shan C, Duan XM, Chen ZH, Liu PP, Song JW, et al. 2020b. A human neutralizing antibody targets the receptor-binding site of SARS-CoV-2. Nature, 584(7819): 120−124. doi: 10.1038/s41586-020-2381-y
    Shu CJ, Xiao K, Sun X. 2020. Structural basis for the high conductivity of microbial pili as potential nanowires. Journal of Nanoscience and Nanotechnology, 20(1): 64−80. doi: 10.1166/jnn.2020.16883
    Song WF, Gui M, Wang XQ, Xiang Y. 2018. Cryo-EM structure of the SARS coronavirus spike glycoprotein in complex with its host cell receptor ACE2. PLoS Pathogens, 14(8): e1007236. doi: 10.1371/journal.ppat.1007236
    Taliun D, Harris DN, Kessler MD, Carlson J, Szpiech ZA, Torres R, et al. 2021. Sequencing of 53,831 diverse genomes from the NHLBI TOPMed program. Nature, 590(7845): 290−299. doi: 10.1038/s41586-021-03205-y
    Tang XL, Wu CC, Li X, Song YH, Yao XM, Wu XK, et al. 2020. On the origin and continuing evolution of SARS-CoV-2. National Science Review, 7(6): 1012−1023. doi: 10.1093/nsr/nwaa036
    The 1000 Genomes Project Consortium. 2015. A global reference for human genetic variation. Nature, 526(7571): 68−74. doi: 10.1038/nature15393
    The UK10K Consortium. 2015. The UK10K project identifies rare variants in health and disease. Nature, 526(7571): 82−90. doi: 10.1038/nature14962
    Tippmann HF. 2004. Analysis for free: comparing programs for sequence analysis. Briefings in Bioinformatics, 5(1): 82−87. doi: 10.1093/bib/5.1.82
    Wang H, Zhang YT, Huang BY, Deng W, Quan YR, Wang WL, et al. 2020a. Development of an inactivated vaccine candidate, BBIBP-CorV, with potent protection against SARS-CoV-2. Cell, 182(3): 713−721. doi: 10.1016/j.cell.2020.06.008
    Wang ML, Cao RY, Zhang LK, Yang XL, Liu J, Xu MY, et al. 2020b. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Research, 30(3): 269−271. doi: 10.1038/s41422-020-0282-0
    Waterhouse A, Bertoni M, Bienert S, Studer G, Tauriello G, Gumienny R, et al. 2018. SWISS-MODEL: homology modelling of protein structures and complexes. Nucleic Acids Research, 46(W1): W296−W303. doi: 10.1093/nar/gky427
    Wrapp D, Wang NS, Corbett KS, Goldsmith JA, Hsieh CL, Abiona O, et al. 2020. Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation. Science, 367(6483): 1260−1263. doi: 10.1126/science.abb2507
    Zhao Y, Zhao ZX, Wang YJ, Zhou YQ, Ma Y, Zuo W. 2020. Single-cell RNA expression profiling of ACE2, the putative receptor of Wuhan 2019-nCov. bioRxiv. doi: 10.1101/2020.01.26.919985.
    Zheng YY, Ma YT, Zhang JY, Xie X. 2020. COVID-19 and the cardiovascular system. Nature Reviews Cardiology, 17(5): 259−260. doi: 10.1038/s41569-020-0360-5
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