Zinuo Chen, Ruikun Du, Jazmin M. Galvan Achi, Lijun Rong, Qinghua Cui. SARS-CoV-2 cell entry and targeted antiviral development[J]. Acta Pharmaceutica Sinica B, 2021, 11(12): 3879-3888

SARS-CoV-2 cell entry and targeted antiviral development
Zinuo Chena, Ruikun Dua,b,c, Jazmin M. Galvan Achid, Lijun Rongd, Qinghua Cuia,b,c
a. College of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan 250355, China;
b. Qingdao Academy of Chinese Medicinal Sciences, Shandong University of Traditional Chinese Medicine, Qingdao 266122, China;
c. Experimental Center, Shandong University of Traditional Chinese Medicine, Jinan 250355, China;
d. Department of Microbiology and Immunology, College of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the pandemic coronavirus disease 2019 (COVID-19), which threatens human health and public safety. In the urgent campaign to develop anti-SARS-CoV-2 therapies, the initial entry step is one of the most appealing targets. In this review, we summarize the current understanding of SARS-CoV-2 cell entry, and the development of targeted antiviral strategies. Moreover, we speculate upon future directions toward next-generation of SARS-CoV-2 entry inhibitors during the upcoming post-pandemic era.
Key words:    SARS-CoV-2    Cell entry    Spike protein    Antiviral development    Post-pandemic   
Received: 2021-03-17     Revised: 2021-04-21
DOI: 10.1016/j.apsb.2021.05.007
Funds: This work was supported by the Drug Innovation Major Project (No. 2018ZX09711001, China), Shandong Provincial Natural Science Foundation, China (No. ZR2020MH383), and Qingdao Social Benefiting Technology Program, China (No. 21-1-4-rkjk-15-nsh).
Corresponding author: Lijun Rong,;Qinghua Cui,;
Author description:
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Zinuo Chen
Ruikun Du
Jazmin M. Galvan Achi
Lijun Rong
Qinghua Cui

[1] Wang C, Horby PW, Hayden FG, Gao GF. A novel coronavirus outbreak of global health concern. Lancet 2020;395:470-473
[2] Zhou P, Yang XL, Wang XG, Hu B, Zhang L, Zhang W, et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 2020;579:270-273
[3] Gorbalenya AE, Baker SC, Baric RS, de Groot RJ, Drosten C, Gulyaeva AA, et al. Severe acute respiratory syndrome-related coronavirus: The species and its viruses - a statement of the Coronavirus Study Group. bioRxiv 2020. Available from:
[4] Wu JT, Leung K, Leung GM. Nowcasting and forecasting the potential domestic and international spread of the 2019-nCoV outbreak originating in Wuhan, China: A modelling study. Lancet 2020;395:689-697
[5] Hui DS, I Azhar E, Madani TA, Ntoumi F, Kock R, Dar O, et al. The continuing 2019-nCoV epidemic threat of novel coronaviruses to global health - The latest 2019 novel coronavirus outbreak in Wuhan, China. Int J Infect Dis 2020;91:264-266
[6] Cui J, Li F, Shi ZL. Origin and evolution of pathogenic coronaviruses. Nat Rev Microbiol 2019;17:181-192
[7] Callaway E. Fast-spreading COVID variant can elude immune responses. Nature 2021. Available from:
[8] Tegally H, Wilkinson E, Giovanetti M, Iranzadeh A, Fonseca V, Giandhari J, et al. Emergence and rapid spread of a new severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) lineage with multiple spike mutations in South Africa. medRxiv 2020. Available from:
[9] Ke Z, Oton J, Qu K, Cortese M, Zila V, McKeane L, et al. Structures and distributions of SARS-CoV-2 spike proteins on intact virions. Nature 2020;588:498-502
[10] Walls AC, Park YJ, Tortorici MA, Wall A, McGuire AT, Veesler D. Structure, function, and antigenicity of the SARS-CoV-2 spike glycoprotein. Cell 2020;181:281-92.e6
[11] White JM, Whittaker GR. Fusion of enveloped viruses in endosomes. Traffic 2016;17:593-614
[12] Burkard C, Verheije MH, Wicht O, van Kasteren SI, van Kuppeveld FJ, Haagmans BL, et al. Coronavirus cell entry occurs through the endo-/lysosomal pathway in a proteolysis-dependent manner. PLoS Pathog 2014;10:e1004502
[13] Madu IG, Roth SL, Belouzard S, Whittaker GR. Characterization of a highly conserved domain within the severe acute respiratory syndrome coronavirus spike protein S2 domain with characteristics of a viral fusion peptide. J Virol 2009;83:7411-7421
[14] Belouzard S, Chu VC, Whittaker GR. Activation of the SARS coronavirus spike protein via sequential proteolytic cleavage at two distinct sites. Proc Natl Acad Sci U S A 2009;106:5871-5876
[15] Li W, Moore MJ, Vasilieva N, Sui J, Wong SK, Berne MA, et al. Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus. Nature 2003;426:450-454
[16] Hoffmann M, Kleine-Weber H, Schroeder S, Kruger N, Herrler T, Erichsen S, et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell 2020;181:271-80.e8
[17] Ou X, Liu Y, Lei X, Li P, Mi D, Ren L, et al. Characterization of spike glycoprotein of SARS-CoV-2 on virus entry and its immune cross-reactivity with SARS-CoV. Nat Commun 2020;11:1620
[18] Wan Y, Shang J, Graham R, Baric RS, Li F. Receptor recognition by the novel coronavirus from Wuhan: An analysis based on decade-long structural studies of SARS coronavirus. J Virol 2020;94:e00127-20
[19] Clausen TM, Sandoval DR, Spliid CB, Pihl J, Perrett HR, Painter CD, et al. SARS-CoV-2 infection depends on cellular heparan sulfate and ACE2. Cell 2020;183:1043-57.e15
[20] Yan R, Zhang Y, Li Y, Xia L, Guo Y, Zhou Q. Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2. Science 2020;367:1444-1448
[21] Shang J, Ye G, Shi K, Wan Y, Luo C, Aihara H, et al. Structural basis of receptor recognition by SARS-CoV-2. Nature 2020;581:221-224
[22] Lan J, Ge J, Yu J, Shan S, Zhou H, Fan S, et al. Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor. Nature 2020;581:215-220
[23] Wang Q, Zhang Y, Wu L, Niu S, Song C, Zhang Z, et al. Structural and functional basis of SARS-CoV-2 entry by using human ACE2. Cell 2020;181:894-904.e9
[24] Wrapp D, Wang N, Corbett KS, Goldsmith JA, Hsieh CL, Abiona O, et al. Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation. Science 2020;367:1260-1263
[25] Hikmet F, Mear L, Edvinsson A, Micke P, Uhlen M, Lindskog C. The protein expression profile of ACE2 in human tissues. Mol Syst Biol 2020;16:e9610
[26] Fu J, Zhou B, Zhang L, Balaji KS, Wei C, Liu X, et al. Expressions and significances of the angiotensin-converting enzyme 2 gene, the receptor of SARS-CoV-2 for COVID-19. Mol Biol Rep 2020;47:4383-4392
[27] Bamberger C, Pankow S, Martinez-Bartolome S, Diedrich J, Park R, Yates J. The host interactome of spike expands the tropism of SARS-CoV-2. bioRxiv 2021. Available from:
[28] Han X, Zhou Z, Fei L, Sun H, Wang R, Chen Y, et al. Construction of a human cell landscape at single-cell level. Nature 2020;581:303-309
[29] Zhang H, Rostami MR, Leopold PL, Mezey JG, O'Beirne SL, Strulovici-Barel Y, et al. Expression of the SARS-CoV-2 ACE2 receptor in the human airway epithelium. Am J Respir Crit Care Med 2020;202:219-229
[30] Jia HP, Look DC, Shi L, Hickey M, Pewe L, Netland J, et al. ACE2 receptor expression and severe acute respiratory syndrome coronavirus infection depend on differentiation of human airway epithelia. J Virol 2005;79:14614-14621
[31] Zou L, Ruan F, Huang M, Liang L, Huang H, Hong Z, et al. SARS-CoV-2 viral load in upper respiratory specimens of infected patients. N Engl J Med 2020;382:1177-1179
[32] Puray-Chavez M, LaPak KM, Schrank TP, Elliott JL, Bhatt DP, Agajanian MJ, et al. Systematic analysis of SARS-CoV-2 infection of an ACE2-negative human airway cell. bioRxiv 2021. Available from:
[33] Wang S, Qiu Z, Hou Y, Deng X, Xu W, Zheng T, et al. AXL is a candidate receptor for SARS-CoV-2 that promotes infection of pulmonary and bronchial epithelial cells. Cell Res 2021;31:126-140
[34] Amraei R, Yin W, Napoleon MA, Suder EL, Berrigan J, Zhao Q, et al. CD209L/L-SIGN and CD209/DC-SIGN act as receptors for SARS-CoV-2 and are differentially expressed in lung and kidney epithelial and endothelial cells. bioRxiv 2020. Available from:
[35] Wei C, Wan L, Yan Q, Wang X, Zhang J, Yang X, et al. HDL-scavenger receptor B type 1 facilitates SARS-CoV-2 entry. Nat Metab 2020;2:1391-1400
[36] Cantuti-Castelvetri L, Ojha R, Pedro LD, Djannatian M, Franz J, Kuivanen S, et al. Neuropilin-1 facilitates SARS-CoV-2 cell entry and infectivity. Science 2020;370:856-860
[37] Baggen J, Persoons L, Vanstreels E, Jansen S, Van Looveren D, Boeckx B, et al. Genome-wide CRISPR screening identifies TMEM106B as a proviral host factor for SARS-CoV-2. Nat Genet 2021;53:435-444
[38] Bayati A, Kumar R, Francis V, McPherson PS. SARS-CoV-2 infects cells following viral entry via clathrin-mediated endocytosis. J Biol Chem 2021;296:100306
[39] Jaimes JA, Andre NM, Chappie JS, Millet JK, Whittaker GR. Phylogenetic analysis and structural modeling of SARS-CoV-2 spike protein reveals an evolutionary distinct and proteolytically sensitive activation loop. J Mol Biol 2020;432:3309-3325
[40] Coutard B, Valle C, de Lamballerie X, Canard B, Seidah NG, Decroly E. The spike glycoprotein of the new coronavirus 2019-nCoV contains a furin-like cleavage site absent in CoV of the same clade. Antiviral Res 2020;176:104742
[41] Hoffmann M, Kleine-Weber H, Pohlmann S. A multibasic cleavage site in the spike protein of SARS-CoV-2 is essential for infection of human lung cells. Mol Cell 2020;78:779-784.e5
[42] Park JE, Li K, Barlan A, Fehr AR, Perlman S, McCray PB, Jr., et al. Proteolytic processing of Middle East respiratory syndrome coronavirus spikes expands virus tropism. Proc Natl Acad Sci U S A 2016;113:12262-12267
[43] Millet JK, Whittaker GR. Host cell entry of Middle East respiratory syndrome coronavirus after two-step, furin-mediated activation of the spike protein. Proc Natl Acad Sci U S A 2014;111:15214-15219
[44] Tse LV, Hamilton AM, Friling T, Whittaker GR. A novel activation mechanism of avian influenza virus H9N2 by furin. J Virol 2014;88:1673-1683
[45] Papa G, Mallery DL, Albecka A, Welch LG, Cattin-Ortola J, Luptak J, et al. Furin cleavage of SARS-CoV-2 Spike promotes but is not essential for infection and cell-cell fusion. PLoS Pathog 2021;17:e1009246
[46] Shang J, Wan Y, Luo C, Ye G, Geng Q, Auerbach A, et al. Cell entry mechanisms of SARS-CoV-2. Proc Natl Acad Sci U S A 2020;117:11727-11734
[47] Wang M, Cao R, Zhang L, Yang X, Liu J, Xu M, et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res 2020;30:269-271
[48] Liu J, Cao R, Xu M, Wang X, Zhang H, Hu H, et al. Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro. Cell Discov 2020;6:16
[49] Fantini J, Di Scala C, Chahinian H, Yahi N. Structural and molecular modelling studies reveal a new mechanism of action of chloroquine and hydroxychloroquine against SARS-CoV-2 infection. Int J Antimicrob Agents 2020;55:105960
[50] Wang X, Cao R, Zhang H, Liu J, Xu M, Hu H, et al. The anti-influenza virus drug, arbidol is an efficient inhibitor of SARS-CoV-2 in vitro. Cell Discov 2020;6:28
[51] Geleris J, Sun Y, Platt J, Zucker J, Baldwin M, Hripcsak G, et al. Observational study of hydroxychloroquine in hospitalized patients with Covid-19. N Engl J Med 2020;382:2411-2418
[52] Watson JA, Tarning J, Hoglund RM, Baud FJ, Megarbane B, Clemessy JL, et al. Concentration-dependent mortality of chloroquine in overdose. Elife 2020;9:e58631
[53] Zhu Z, Lu Z, Xu T, Chen C, Yang G, Zha T, et al. Arbidol monotherapy is superior to lopinavir/ritonavir in treating COVID-19. J Infect 2020;81:e21-e23
[54] Deng L, Li C, Zeng Q, Liu X, Li X, Zhang H, et al. Arbidol combined with LPV/r versus LPV/r alone against Corona Virus Disease 2019: A retrospective cohort study. J Infect 2020;81:e1-5
[55] Wang Z, Chen X, Lu Y, Chen F, Zhang W. Clinical characteristics and therapeutic procedure for four cases with 2019 novel coronavirus pneumonia receiving combined Chinese and Western medicine treatment. Biosci Trends 2020;14:64-68
[56] Corti D, Misasi J, Mulangu S, Stanley DA, Kanekiyo M, Wollen S, et al. Protective monotherapy against lethal Ebola virus infection by a potently neutralizing antibody. Science 2016;351:1339-1342
[57] Saphire EO, Schendel SL, Gunn BM, Milligan JC, Alter G. Antibody-mediated protection against Ebola virus. Nat Immunol 2018;19:1169-1178
[58] Moekotte AL, Huson MA, van der Ende AJ, Agnandji ST, Huizenga E, Goorhuis A, et al. Monoclonal antibodies for the treatment of Ebola virus disease. Expert Opin Investig Drugs 2016;25:1325-1335
[59] Tian X, Li C, Huang A, Xia S, Lu S, Shi Z, et al. Potent binding of 2019 novel coronavirus spike protein by a SARS coronavirus-specific human monoclonal antibody. Emerg Microbes Infect 2020;9:382-385
[60] Pinto D, Park YJ, Beltramello M, Walls AC, Tortorici MA, Bianchi S, et al. Cross-neutralization of SARS-CoV-2 by a human monoclonal SARS-CoV antibody. Nature 2020;583:290-295
[61] Brouwer PJM, Caniels TG, van der Straten K, Snitselaar JL, Aldon Y, Bangaru S, et al. Potent neutralizing antibodies from COVID-19 patients define multiple targets of vulnerability. Science 2020;369:643-650
[62] Cao Y, Su B, Guo X, Sun W, Deng Y, Bao L, et al. Potent neutralizing antibodies against SARS-CoV-2 identified by high-throughput single-cell sequencing of convalescent patients’ B cells. Cell 2020;182:73-84.e16
[63] Ju B, Zhang Q, Ge J, Wang R, Sun J, Ge X, et al. Human neutralizing antibodies elicited by SARS-CoV-2 infection. Nature 2020;584:115-119
[64] Kreer C, Zehner M, Weber T, Ercanoglu MS, Gieselmann L, Rohde C, et al. Longitudinal isolation of potent near-germline SARS-CoV-2-neutralizing antibodies from COVID-19 patients. Cell 2020;182:843-854.e12
[65] Robbiani DF, Gaebler C, Muecksch F, Lorenzi JCC, Wang Z, Cho A, et al. Convergent antibody responses to SARS-CoV-2 in convalescent individuals. Nature 2020;584:437-442
[66] Rogers TF, Zhao F, Huang D, Beutler N, Burns A, He WT, et al. Isolation of potent SARS-CoV-2 neutralizing antibodies and protection from disease in a small animal model. Science 2020;369:956-963
[67] Kreye J, Reincke SM, Kornau HC, Sanchez-Sendin E, Corman VM, Liu H, et al. A therapeutic non-self-reactive SARS-CoV-2 antibody protects from lung pathology in a COVID-19 hamster model. Cell 2020;183:1058-1069.e19
[68] Liu L, Wang P, Nair MS, Yu J, Rapp M, Wang Q, et al. Potent neutralizing antibodies against multiple epitopes on SARS-CoV-2 spike. Nature 2020;584:450-456
[69] Chi X, Yan R, Zhang J, Zhang G, Zhang Y, Hao M, et al. A neutralizing human antibody binds to the N-terminal domain of the Spike protein of SARS-CoV-2. Science 2020;369:650-655
[70] Tortorici MA, Beltramello M, Lempp FA, Pinto D, Dang HV, Rosen LE, et al. Ultrapotent human antibodies protect against SARS-CoV-2 challenge via multiple mechanisms. Science 2020;370:950-957
[71] Chen P, Nirula A, Heller B, Gottlieb RL, Boscia J, Morris J, et al. SARS-CoV-2 neutralizing antibody LY-CoV555 in outpatients with Covid-19. N Engl J Med 2021;384:229-237
[72] Hansen J, Baum A, Pascal KE, Russo V, Giordano S, Wloga E, et al. Studies in humanized mice and convalescent humans yield a SARS-CoV-2 antibody cocktail. Science 2020;369:1010-1014
[73] Gottlieb RL, Nirula A, Chen P, Boscia J, Heller B, Morris J, et al. Effect of bamlanivimab as monotherapy or in combination with etesevimab on viral load in patients with mild to moderate COVID-19: A randomized clinical trial. JAMA 2021;325:632-644
[74] Kim C, Ryu DK, Lee J, Kim YI, Seo JM, Kim YG, et al. A therapeutic neutralizing antibody targeting receptor binding domain of SARS-CoV-2 spike protein. Nat Commun 2021;12:288
[75] An EUA for bamlanivimab and etesevimab for COVID-19. Med Lett Drugs Ther 2021;63:49-50
[76] Jones BE, Brown-Augsburger PL, Corbett KS, Westendorf K, Davies J, Cujec TP, et al. The neutralizing antibody, LY-CoV555, protects against SARS-CoV-2 infection in non-human primates. Sci Transl Med 2021;13:eabf1906
[77] Baum A, Ajithdoss D, Copin R, Zhou A, Lanza K, Negron N, et al. REGN-COV2 antibodies prevent and treat SARS-CoV-2 infection in rhesus macaques and hamsters. Science 2020;370:1110-1115
[78] Weinreich DM, Sivapalasingam S, Norton T, Ali S, Gao H, Bhore R, et al. REGN-COV2, a neutralizing antibody cocktail, in outpatients with Covid-19. N Engl J Med 2021;384:238-251
[79] FDA. Coronavirus (COVID-19) update: FDA revokes emergency use authorization for monoclonal antibody bamlanivimab, 2021. Available from:
[80] Tuccori M, Ferraro S, Convertino I, Cappello E, Valdiserra G, Blandizzi C, et al. Anti-SARS-CoV-2 neutralizing monoclonal antibodies: Clinical pipeline. MAbs 2020;12:1854149
[81] Hanke L, Vidakovics Perez L, Sheward DJ, Das H, Schulte T, Moliner-Morro A, et al. An alpaca nanobody neutralizes SARS-CoV-2 by blocking receptor interaction. Nat Commun 2020;11:4420
[82] Huo J, Le Bas A, Ruza RR, Duyvesteyn HME, Mikolajek H, Malinauskas T, et al. Neutralizing nanobodies bind SARS-CoV-2 spike RBD and block interaction with ACE2. Nat Struct Mol Biol 2020;27:846-854
[83] Schoof M, Faust B, Saunders RA, Sangwan S, Rezelj V, Hoppe N, et al. An ultrapotent synthetic nanobody neutralizes SARS-CoV-2 by stabilizing inactive Spike. Science 2020;370:1473-1479
[84] Wrapp D, De Vlieger D, Corbett KS, Torres GM, Wang N, Van Breedam W, et al. Structural basis for potent neutralization of betacoronaviruses by single-domain camelid antibodies. Cell 2020;181:1004-15.e15
[85] Xiang Y, Nambulli S, Xiao Z, Liu H, Sang Z, Duprex WP, et al. Versatile and multivalent nanobodies efficiently neutralize SARS-CoV-2. Science 2020;370:1479-1484
[86] Wu Y, Li C, Xia S, Tian X, Kong Y, Wang Z, et al. Identification of human single-domain antibodies against SARS-CoV-2. Cell Host Microbe 2020;27:891-898.e5
[87] Czajka TF, Vance DJ, Mantis NJ. Slaying SARS-CoV-2 one (single-domain) antibody at a time. Trends Microbiol 2021;29:195-203
[88] Li W, Schafer A, Kulkarni SS, Liu X, Martinez DR, Chen C, et al. High potency of a bivalent human VH domain in SARS-CoV-2 animal models. Cell 2020;183:429-441.e16
[89] Monteil V, Kwon H, Prado P, Hagelkruys A, Wimmer RA, Stahl M, et al. Inhibition of SARS-CoV-2 infections in engineered human tissues using clinical-grade soluble human ACE2. Cell 2020;181:905-13.e7
[90] Chan KK, Dorosky D, Sharma P, Abbasi SA, Dye JM, Kranz DM, et al. Engineering human ACE2 to optimize binding to the spike protein of SARS coronavirus 2. Science 2020;369:1261-1265
[91] Basit A, Ali T, Rehman SU. Truncated human angiotensin converting enzyme 2; a potential inhibitor of SARS-CoV-2 spike glycoprotein and potent COVID-19 therapeutic agent. J Biomol Struct Dyn 2021;39:3605-14
[92] Guo L, Bi W, Wang X, Xu W, Yan R, Zhang Y, et al. Engineered trimeric ACE2 binds viral spike protein and locks it in "Three-up" conformation to potently inhibit SARS-CoV-2 infection. Cell Res 2021;31:98-100
[93] Lei C, Qian K, Li T, Zhang S, Fu W, Ding M, et al. Neutralization of SARS-CoV-2 spike pseudotyped virus by recombinant ACE2-Ig. Nat Commun 2020;11:2070
[94] Iwanaga N, Cooper L, Rong L, Beddingfield B, Crabtree J, Tripp RA, et al. Novel ACE2-IgG1 fusions with improved activity against SARS-CoV2. bioRxiv 2020. Available from:
[95] Karoyan P, Vieillard V, Gomez-Morales L, Odile E, Guihot A, Luyt CE, et al. Human ACE2 peptide-mimics block SARS-CoV-2 pulmonary cells infection. Commun Biol 2021;4:197
[96] Curreli F, Victor SMB, Ahmed S, Drelich A, Tong X, Tseng CK, et al. Stapled peptides based on human angiotensin-converting enzyme 2 (ACE2) potently inhibit SARS-CoV-2 infection in vitro. mBio 2020;11:e02451-20
[97] Panda SK, Sen Gupta PS, Biswal S, Ray AK, Rana MK. ACE-2-derived biomimetic peptides for the inhibition of spike protein of SARS-CoV-2. J Proteome Res 2021;20:1296-1303
[98] Peter EK, Schug A. The inhibitory effect of a coronavirus spike protein fragment with ACE2. Biophys J 2020;120:1001-1010
[99] Liu S, Xiao G, Chen Y, He Y, Niu J, Escalante CR, et al. Interaction between heptad repeat 1 and 2 regions in spike protein of SARS-associated coronavirus: Implications for virus fusogenic mechanism and identification of fusion inhibitors. Lancet 2004;363:938-947
[100] Lu L, Liu Q, Zhu Y, Chan KH, Qin L, Li Y, et al. Structure-based discovery of Middle East respiratory syndrome coronavirus fusion inhibitor. Nat Commun 2014;5:3067
[101] Xia S, Zhu Y, Liu M, Lan Q, Xu W, Wu Y, et al. Fusion mechanism of 2019-nCoV and fusion inhibitors targeting HR1 domain in spike protein. Cell Mol Immunol 2020;17:765-767
[102] Zhu Y, Yu D, Yan H, Chong H, He Y. Design of potent membrane fusion inhibitors against SARS-CoV-2, an emerging coronavirus with high fusogenic activity. J Virol 2020;94:e00635-20
[103] Xia S, Yan L, Xu W, Agrawal AS, Algaissi A, Tseng CK, et al. A pan-coronavirus fusion inhibitor targeting the HR1 domain of human coronavirus spike. Sci Adv 2019;5:eaav4580
[104] Xia S, Liu M, Wang C, Xu W, Lan Q, Feng S, et al. Inhibition of SARS-CoV-2 (previously 2019-nCoV)infection by a highly potent pan-coronavirus fusion inhibitor targeting its spike protein that harbors a high capacity to mediate membrane fusion. Cell Res 2020;30:343-355
[105] de Vries RD, Schmitz KS, Bovier FT, Predella C, Khao J, Noack D, et al. Intranasal fusion inhibitory lipopeptide prevents direct-contact SARS-CoV-2 transmission in ferrets. Science 2021;371:1379-1382
[106] Hoffmann M, Schroeder S, Kleine-Weber H, Muller MA, Drosten C, Pohlmann S. Nafamostat mesylate blocks activation of SARS-CoV-2: New treatment option for COVID-19. Antimicrob Agents Chemother 2020;64:e00754-20
[107] Wang Y, Zhang Y, Chen X, Xue K, Zhang T, Ren X. Evaluating the efficacy and safety of bromhexine hydrochloride tablets in treating pediatric COVID-19: A protocol for meta-analysis and systematic review. Medicine (Baltimore) 2020;99:e22114
[108] Hu J, Gao Q, He C, Huang A, Tang N, Wang K. Development of cell-based pseudovirus entry assay to identify potential viral entry inhibitors and neutralizing antibodies against SARS-CoV-2. Genes Dis 2020;7:551-557
[109] Liu T, Luo S, Libby P, Shi GP. Cathepsin L-selective inhibitors: A potentially promising treatment for COVID-19 patients. Pharmacol Ther 2020;213:107587
[110] Zhao MM, Yang WL, Yang FY, Zhang L, Huang WJ, Hou W, et al. Cathepsin L plays a key role in SARS-CoV-2 infection in humans and humanized mice and is a promising target for new drug development. Signal Transduct Target Ther 2021;6:134
[111] Cheng YW, Chao TL, Li CL, Chiu MF, Kao HC, Wang SH, et al. Furin inhibitors block SARS-CoV-2 spike protein cleavage to suppress virus production and cytopathic effects. Cell Rep 2020;33:108254
[112] Choudhary S, Malik YS, Tomar S. Identification of SARS-CoV-2 cell entry inhibitors by drug repurposing using in silico structure-based virtual screening approach. Front Immunol 2020;11:1664
[113] Br B, Damle H, Ganju S, Damle L. In silico screening of known small molecules to bind ACE2 specific RBD on Spike glycoprotein of SARS-CoV-2 for repurposing against COVID-19. F1000Res 2020;9:663
[114] Farouk AE, Hassan Baig M, Imran Khan M, Tae Hwan P, Alotaibi SS, Dong JJ. Screening of inhibitors against SARS-CoV-2 spike protein and their capability to block the viral entry mechanism: A Viroinformatics study. Saudi J Biol Sci 2021;28:3262-9
[115] Gangadevi S, Badavath VN, Thakur A, Yin N, De Jonghe S, Acevedo O, et al. Kobophenol A inhibits binding of host ACE2 receptor with spike RBD domain of SARS-CoV-2, a lead compound for blocking COVID-19. J Phys Chem Lett 2021;12:1793-1802
[116] Maffucci I, Contini A. In silico drug repurposing for SARS-CoV-2 main proteinase and spike proteins. J Proteome Res 2020;19:4637-4648
[117] Wu C, Liu Y, Yang Y, Zhang P, Zhong W, Wang Y, et al. Analysis of therapeutic targets for SARS-CoV-2 and discovery of potential drugs by computational methods. Acta Pharm Sin B 2020;10:766-788
[118] Lin C, Li Y, Yuan M, Huang M, Liu C, Du H, et al. Ceftazidime is a potential drug to inhibit SARS-CoV-2 infection in vitro by blocking spike protein-ACE2 interaction. Signal Transduct Target Ther 2021;6:198
[119] Yang C, Pan X, Xu X, Cheng C, Huang Y, Li L, et al. Salvianolic acid C potently inhibits SARS-CoV-2 infection by blocking the formation of six-helix bundle core of spike protein. Signal Transduct Target Ther 2020;5:220
[120] Kemp S, Meng B, Ferreira I, Datir R, Harvey W, Collier D, et al. Recurrent emergence and transmission of a SARS-CoV-2 Spike deletion H69/V70. bioRxiv 2021. Available from:
[121] Korber B, Fischer WM, Gnanakaran S, Yoon H, Theiler J, Abfalterer W, et al. Tracking changes in SARS-CoV-2 spike: Evidence that D614G increases infectivity of the COVID-19 virus. Cell 2020;182:812-827.e19
[122] Chen RE, Zhang X, Case JB, Winkler ES, Liu Y, VanBlargan LA, et al. Resistance of SARS-CoV-2 variants to neutralization by monoclonal and serum-derived polyclonal antibodies. Nat Med 2021;27:717-726
[123] Diamond M, Chen R, Xie X, Case J, Zhang X, VanBlargan L, et al. SARS-CoV-2 variants show resistance to neutralization by many monoclonal and serum-derived polyclonal antibodies. Res Sq 2021. Available from:
[124] Wang P, Nair MS, Liu L, Iketani S, Luo Y, Guo Y, et al. Antibody Resistance of SARS-CoV-2 Variants B.1.351 and B.1.1.7. Nature 2021. Available from:
[125] Li Y, Ma ML, Lei Q, Wang F, Hong W, Lai DY, et al. Linear epitope landscape of the SARS-CoV-2 Spike protein constructed from 1,051 COVID-19 patients. Cell Rep 2021;34:108915
[126] Du R, Cui Q, Rong L. Flu Universal Vaccines: New Tricks on an Old Virus. Virol Sin 2021;36:13-24
[127] Impagliazzo A, Milder F, Kuipers H, Wagner MV, Zhu X, Hoffman RM, et al. A stable trimeric influenza hemagglutinin stem as a broadly protective immunogen. Science 2015;349:1301-1306
[128] Yassine HM, Boyington JC, McTamney PM, Wei CJ, Kanekiyo M, Kong WP, et al. Hemagglutinin-stem nanoparticles generate heterosubtypic influenza protection. Nat Med 2015;21:1065-1070
[129] Eggink D, Goff PH, Palese P. Guiding the immune response against influenza virus hemagglutinin toward the conserved stalk domain by hyperglycosylation of the globular head domain. J Virol 2014;88:699-704
[130] Lin SC, Lin YF, Chong P, Wu SC. Broader neutralizing antibodies against H5N1 viruses using prime-boost immunization of hyperglycosylated hemagglutinin DNA and virus-like particles. PLoS One 2012;7:e39075
[131] Gurevich EV, Gurevich VV. Therapeutic potential of small molecules and engineered proteins. Handb Exp Pharmacol 2014;219:1-12
[132] Schafer A, Xiong R, Cooper L, Nowar R, Lee H, Li Y, et al. Evidence for distinct mechanisms of small molecule inhibitors of filovirus entry. PLoS Pathog 2021;17:e1009312
[133] Cheng H, Schafer A, Soloveva V, Gharaibeh D, Kenny T, Retterer C, et al. Identification of a coumarin-based antihistamine-like small molecule as an anti-filoviral entry inhibitor. Antiviral Res 2017;145:24-32
[134] Cui Q, Cheng H, Xiong R, Zhang G, Du R, Anantpadma M, et al. Identification of diaryl-quinoline compounds as entry inhibitors of Ebola virus. Viruses 2018;10:678
[135] Kalathiya U, Padariya M, Mayordomo M, Lisowska M, Nicholson J, Singh A, et al. Highly conserved homotrimer cavity formed by the SARS-CoV-2 spike glycoprotein: A novel binding site. J Clin Med 2020;9:1473
[136] Hu B, Guo H, Zhou P, Shi ZL. Characteristics of SARS-CoV-2 and COVID-19. Nat Rev Microbiol 2021;19:141-154
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