Molecular Elucidation and Therapeutic Targeting for Combating COVID-19: Current Scenario and Future Prospective

Page: [894 - 907] Pages: 14

  • * (Excluding Mailing and Handling)

Abstract

The coronavirus disease 2019 (COVID-19) is a contagious disease that is caused by a novel coronavirus. The human coronavirus (HCoV) is recognized as one of the most rapidly evolving viruses owing to its high genomic nucleotide substitution rates and recombination. Among the severe acute respiratory syndrome (SARS) and Middle- East respiratory syndrome (MERS), COVID-19 has spread more rapidly and increased the level of globalization and adaptation of the virus in every environmental condition due to their high rate of molecular diversity. The whole article highlights the general characteristics of coronavirus, their molecular diversity, and molecular protein targeting against COVID-19 with their newer approaches. Through this review, an attempt has been made to critically evaluate the recent advances and future aspects that are helpful to the treatment of COVID-19 based on the present understanding of SARS-CoV-2 infections, which may offer new insights and potential therapeutic targets for the treatment of COVID-19.

Keywords: COVID-19, molecular targeting, molecular diversity, SARS-CoV-2, clinical trials, future prospective.

[1]
Ksiazek TG, Erdman D, Goldsmith CS, et al. A novel coronavirus associated with severe acute respiratory syndrome. N Engl J Med 2003; 348: 1953-66.
[2]
Pyrc K, Berkhout B, Van Der Hoek L. Identification of new human coronaviruses. Expert review of anti-infective therapy 2007; 5(2): 245-53.
[3]
Dijkman R, Jebbink MF, Koekkoek SM, et al. Isolation and characterization of current human coronavirus strains in primary human epithelial cell cultures reveal differences in target cell tropism. Journal of virology 2013; 87(11): 6081-90.
[http://dx.doi.org/10.1128/JVI.03368-12]
[4]
Su S, Wong G, Shi W, et al. Epidemiology, genetic recombination, and pathogenesis of coronaviruses. Trends Microbiol 2016; 24(6): 490-502.
[http://dx.doi.org/10.1016/j.tim.2016.03.003] [PMID: 27012512]
[5]
Forni D, Cagliani R, Clerici M, Sironi M. Molecular evolution of human coronavirus genomes. Trends in microbiology 2017; 25(1): 35-48.
[6]
Ye ZW, Yuan S, Yuen KS, Fung SY, Chan CP, Jin DY. Zoonotic origins of human coronaviruses. Int J Biol Sci 2020; 16(10): 1686-97.
[http://dx.doi.org/10.7150/ijbs.45472] [PMID: 32226286]
[7]
Monchatre-Leroy E, Boué F, Boucher JM, et al. Identification of alpha and beta coronavirus in wildlife species in France: bats, rodents, rabbits, and hedgehogs. Viruses 2017; 9(12): 364.
[http://dx.doi.org/10.3390/v9120364] [PMID: 29186061]
[8]
Wang N, Shang J, Jiang S, Du L. Subunit vaccines against emerging pathogenic human coronaviruses. Front Microbiol 2020; 11: 298.
[http://dx.doi.org/10.3389/fmicb.2020.00298] [PMID: 32265848]
[9]
Lai CC, Shih TP, Ko WC, Tang HJ, Hsueh PR. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and coronavirus disease-2019 (COVID-19): The epidemic and the challenges. Int J Antimicrob Agents 2020; 55(3): 105924.
[http://dx.doi.org/10.1016/j.ijantimicag.2020.105924] [PMID: 32081636]
[10]
Gaunt ER, Hardie A, Claas EC, Simmonds P, Templeton KE. Epidemiology and clinical presentations of the four human coronaviruses 229E, HKU1, NL63, and OC43 detected over 3 years using a novel multiplex real-time PCR method. J Clin Microbiol 2010; 48(8): 2940-7.
[http://dx.doi.org/10.1128/JCM.00636-10] [PMID: 20554810]
[11]
Kin N, Miszczak F, Lin W, Gouilh MA, Vabret A. EPICOREM Consortium Genomic analysis of 15 human coronaviruses OC43 (HCoV-OC43s) circulating in France from 2001 to 2013 reveals a high intra-specific diversity with new recombinant genotypes. Viruses 2015; 7(5): 2358-77.
[http://dx.doi.org/10.3390/v7052358] [PMID: 26008694]
[12]
Walsh EE, Shin JH, Falsey AR. Clinical impact of human coronaviruses 229E and OC43 infection in diverse adult populations. J Infect Dis 2013; 208(10): 1634-42.
[http://dx.doi.org/10.1093/infdis/jit393] [PMID: 23922367]
[13]
Gorse GJ, O’Connor TZ, Hall SL, Vitale JN, Nichol KL. Human coronavirus and acute respiratory illness in older adults with chronic obstructive pulmonary disease. J Infect Dis 2009; 199(6): 847-57.
[http://dx.doi.org/10.1086/597122] [PMID: 19239338]
[14]
Bonavia A, Zelus BD, Wentworth DE, Talbot PJ, Holmes KV. Identification of a receptor-binding domain of the spike glycoprotein of human coronavirus HCoV-229E. J Virol 2003; 77(4): 2530-8.
[http://dx.doi.org/10.1128/JVI.77.4.2530-2538.2003] [PMID: 12551991]
[15]
Wevers BA, van der Hoek L. Recently discovered human coronaviruses. Clin Lab Med 2009; 29(4): 715-24.
[http://dx.doi.org/10.1016/j.cll.2009.07.007] [PMID: 19892230]
[16]
Masters PS. The molecular biology of coronaviruses advances in virus research. Massachusetts, MA, USA: Academic Press 2006; Vol. 66: pp. 193-292.
[17]
van der Hoek L. Human coronaviruses: what do they cause? Antivir Ther 2007; 12(4 Pt B): 651-8.
[PMID: 17944272]
[18]
Vijgen L, Keyaerts E, Moës E, Maes P, Duson G, Van Ranst M. Development of one-step, real-time, quantitative reverse transcriptase PCR assays for absolute quantitation of human coronaviruses OC43 and 229E. J Clin Microbiol 2005; 43(11): 5452-6.
[http://dx.doi.org/10.1128/JCM.43.11.5452-5456.2005] [PMID: 16272469]
[19]
Oany AR, Emran AA, Jyoti TP. Design of an epitope-based peptide vaccine against spike protein of human coronavirus: an in silico approach. Drug Des Devel Ther 2014; 8: 1139-49.
[http://dx.doi.org/10.2147/DDDT.S67861] [PMID: 25187696]
[20]
Zhang H, Penninger JM, Li Y, Zhong N, Slutsky AS. Angiotensin-converting enzyme 2 (ACE2) as a SARS-CoV-2 receptor: molecular mechanisms and potential therapeutic target. Intensive Care Med 2020; 46(4): 586-90.
[http://dx.doi.org/10.1007/s00134-020-05985-9] [PMID: 32125455]
[21]
Yin Y, Wunderink RG. Respirology. MERS, SARS and coronaviruses 2018; 130-7.
[22]
Liu DX, Fung TS, Chong KKL, Shukla A, Hilgenfeld R. Accessory proteins of SARS-CoV and other coronaviruses. Antiviral Res 2014; 109: 97-109.
[http://dx.doi.org/10.1016/j.antiviral.2014.06.013] [PMID: 24995382]
[23]
Lim YX, Ng YL, Tam JP, Liu DX. Human coronaviruses: a review of virus-host interactions. Diseases 2016; 4(3): 26.
[http://dx.doi.org/10.3390/diseases4030026] [PMID: 28933406]
[24]
Fung SY, Yuen KS, Ye ZW, Chan CP, Jin DY. A tug-of-war between severe acute respiratory syndrome coronavirus 2 and host antiviral defence: lessons from other pathogenic viruses. Emerg Microbes Infect 2020; 9(1): 558-70.
[http://dx.doi.org/10.1080/22221751.2020.1736644] [PMID: 32172672]
[25]
Farsani SM, Dijkman R, Jebbink MF, et al. The first complete genome sequences of clinical isolates of human coronavirus 229E. Virus Genes 2012; 45(3): 433-9.
[http://dx.doi.org/10.1007/s11262-012-0807-9] [PMID: 22926811]
[26]
Pyrc K, Jebbink MF, Berkhout B, van der Hoek L. Genome structure and transcriptional regulation of human coronavirus NL63. Virol J 2004; 1: 7.
[http://dx.doi.org/10.1186/1743-422X-1-7] [PMID: 15548333]
[27]
Gerna G, Campanini G, Rovida F, et al. Genetic variability of human coronavirus OC43-, 229E-, and NL63-like strains and their association with lower respiratory tract infections of hospitalized infants and immunocompromised patients. J Med Virol 2006; 78(7): 938-49.
[http://dx.doi.org/10.1002/jmv.20645] [PMID: 16721849]
[28]
Zhang SF, Tuo JL, Huang XB, et al. Epidemiology characteristics of human coronaviruses in patients with respiratory infection symptoms and phylogenetic analysis of HCoV-OC43 during 2010-2015 in Guangzhou. PLoS One 2018; 13(1): e0191789.
[http://dx.doi.org/10.1371/journal.pone.0191789] [PMID: 29377913]
[29]
Wu H-S, Hsieh YC, Su IJ, et al. Early detection of antibodies against various structural proteins of the SARS-associated coronavirus in SARS patients. J Biomed Sci 2004; 11(1): 117-26.
[http://dx.doi.org/10.1007/BF02256554] [PMID: 14730215]
[30]
Patrick CY. Characterization and complete genome sequence of a novel coronavirus, coronavirus HKU1, from patients with pneumonia. J Virol 2005; 79(2): 884-95.
[31]
Furuse Y, Okamoto M, Oshitani H. Conservation of nucleotide sequences for molecular diagnosis of Middle East respiratory syndrome coronavirus, 2015. Int J Infect Dis 2015; 40: 25-7.
[http://dx.doi.org/10.1016/j.ijid.2015.09.018] [PMID: 26432410]
[32]
Nowotny N, Kolodziejek J. Middle East respiratory syndrome coronavirus (MERS-CoV) in dromedary camels, Oman, 2013. Euro Surveill 2014; 19(16): 20781.
[http://dx.doi.org/10.2807/1560-7917.ES2014.19.16.20781] [PMID: 24786259]
[33]
Li Dandan, Zhang Jiawei, Li Jinming. Primer design for quantitative real-time PCR for the emerging Coronavirus SARS-CoV-2 2020; 10(16): 7150-62.
[34]
Dhama K, Sharun K, Tiwari R, et al. COVID-19, an emerging coronavirus infection: advances and prospects in designing and developing vaccines, immunotherapeutics, and therapeutics. Hum Vaccin Immunother 2020; 16(6): 1232-8.
[http://dx.doi.org/10.1080/21645515.2020.1735227] [PMID: 32186952]
[35]
Fehr AR, Perlman S. Coronaviruses: an overview of their replication and pathogenesis. New York: Humana Press 2015; pp. 1-23.
[36]
Guo YR, Cao QD, Hong ZS, et al. The origin, transmission and clinical therapies on coronavirus disease 2019 (COVID-19) outbreak–an update on the status. Mil Med Res 2020; 7(1): 1-10.
[http://dx.doi.org/10.1186/s40779-020-00240-0] [PMID: 31928528]
[37]
Walls AC, Park YJ, Tortorici MA, Wall A, McGuire AT, Veesler D. Structure, function, andantigenicity of the SARS-CoV-2 spike glycoprotein. Cell 2020; 181(2): 281-92.
[http://dx.doi.org/10.1016/j.cell.2020.02.058]
[38]
Neuman BW, Kiss G, Kunding AH, et al. A structural analysis of M protein in coronavirus assembly and morphology. J Struct Biol 2011; 174(1): 11-22.
[http://dx.doi.org/10.1016/j.jsb.2010.11.021] [PMID: 21130884]
[39]
Schoeman D, Fielding BC. Coronavirus envelope protein: current knowledge. Virol J 2019; 16(1): 69.
[http://dx.doi.org/10.1186/s12985-019-1182-0] [PMID: 31133031]
[40]
Venkatagopalan P, Daskalova SM, Lopez LA, Dolezal KA, Hogue BG. Coronavirus envelope (E) protein remains at the site of assembly. Virology 2015; 478: 75-85.
[http://dx.doi.org/10.1016/j.virol.2015.02.005] [PMID: 25726972]
[41]
Cong Y, Ulasli M, Schepers H, et al. Nucleocapsid protein recruitment to replication-transcription complexes plays a crucial role in coronaviral life cycle. J Virol 2020; 94(4): e01925-19.
[http://dx.doi.org/10.1128/JVI.01925-19] [PMID: 31776274]
[42]
Ahmed SF, Quadeer AA, McKay MR. Preliminary identification of potential vaccine targets for the COVID-19 coronavirus (SARS-CoV-2) based on SARS-CoV immunological studies. Viruses 2020; 12(3): 254.
[http://dx.doi.org/10.3390/v12030254] [PMID: 32106567]
[43]
Biswas S, Chatterjee S, Dey T, et al. In silico approach for peptide vaccine design for CoVID 19. MOLNET’20 Conference on molecular, biomedical, and computational Sciences and Engineering, USA 2020.
[http://dx.doi.org/10.3390/mol2net-06-06787]
[44]
Cava C, Bertoli G, Castiglioni I. In silico discovery of candidate drugs against covid-19. Viruses 2020; 12(4): 404.
[http://dx.doi.org/10.3390/v12040404] [PMID: 32268515]
[45]
Burrell LM, Johnston CI, Tikellis C, Cooper ME. ACE2, a new regulator of the renin-angiotensin system. Trends Endocrinol Metab 2004; 15(4): 166-9.
[http://dx.doi.org/10.1016/j.tem.2004.03.001] [PMID: 15109615]
[46]
The gene ontology consortium. The gene ontology resource: 20 years and still going strong. Nucleic Acids Res 2019; 47(D1): D330-8.
[http://dx.doi.org/10.1093/nar/gky1055] [PMID: 30395331]
[47]
Manzoor R, Kuroda K, Yoshida R, et al. Heat shock protein 70 modulates influenza A virus polymerase activity. J Biol Chem 2014; 289(11): 7599-614.
[http://dx.doi.org/10.1074/jbc.M113.507798] [PMID: 24474693]
[48]
Vaidya B, Cho SY, Oh KS, et al. Effectiveness of Periodic Treatment of Quercetin against Influenza A Virus H1N1 through Modulation of Protein Expression. J Agric Food Chem 2016; 64(21): 4416-25.
[http://dx.doi.org/10.1021/acs.jafc.6b00148] [PMID: 27157719]
[49]
Esfandiarei M, Suarez A, Amaral A, et al. Novel role for integrin-linked kinase in modulation of coxsackievirus B3 replication and virus-induced cardiomyocyte injury. Circ Res 2006; 99(4): 354-61.
[http://dx.doi.org/10.1161/01.RES.0000237022.72726.01] [PMID: 16840719]
[50]
Osseman Q, Gallucci L, Au S, et al. The chaperone dynein LL1 mediates cytoplasmic transport of empty and mature hepatitis B virus capsids. J Hepatol 2018; 68(3): 441-8.
[http://dx.doi.org/10.1016/j.jhep.2017.10.032] [PMID: 29113909]
[51]
Chang YC, Tung YA, Lee KH, et al. Potential therapeutic agents for COVID-19 based on the analysis of protease and RNA polymerase docking. Preprint 2020.
[52]
Vincent MJ, Bergeron E, Benjannet S, et al. Chloroquine is a potent inhibitor of SARS coronavirus infection and spread. Virol J 2005; 2(2): 69.
[http://dx.doi.org/10.1186/1743-422X-2-69] [PMID: 16115318]
[53]
Devaux CA, Rolain JM, Colson P, Raoult D. New insights on the antiviral effects of chloroquine against coronavirus: what to expect for COVID-19? Int J Antimicrob Agents 2020; 55(5): 105938.
[http://dx.doi.org/10.1016/j.ijantimicag.2020.105938] [PMID: 32171740]
[54]
Kadioglu O, Saeed M, Johannes Greten H, Efferth T. Identification of novel compounds against three targets of SARS CoV-2 coronavirus by combined virtual screening and supervised machine learning. Comput Biol Med 2021; 133: 1043-59.
[55]
Rane JS, Chatterjee A, Kumar A, Ray S. Targeting SARS-CoV-2 spike protein of COVID-19 with naturally occurring phytochemicals: an in silco study for drug development. 2020. J Biomol Struct Dynam 2021; 39(16): 6306-16.
[56]
Khan SA, Zia K, Ashraf S, Uddin R, Ul-Haq Z. Identification of chymotrypsin-like protease inhibitors of SARS-CoV-2 via integrated computational approach. J Biomol Struct Dyn 2020; 39(7): 2607-16.
[PMID: 32238094]
[57]
Shekhar T. Virtual Screening based prediction of potential drugs for COVID-19. Preprint 2020.
[58]
Arya R, Das A, Prashar V, Kumar M. Potential inhibitors against papain-like protease of novel coronavirus (SARS-CoV-2) from FDA approved drugs. Chem RXIV 2020.
[59]
Cavasotto CN, Di Filippo JI. In silico Drug Repurposing for COVID-19: Targeting SARS-CoV-2 Proteins through Docking and Quantum Mechanical Scoring. Mol Inform 2020; 40(1): e2000115.
[60]
Vardhan S, Sahoo SK. Searching inhibitors for three important proteins of COVID-19 through molecular docking studies. arXiv preprint 2020.
[61]
Shulla A, Heald-Sargent T, Subramanya G, Zhao J, Perlman S, Gallagher T. A transmembrane serine protease is linked to the severe acute respiratory syndrome coronavirus receptor and activates virus entry. J Virol 2011; 85(2): 873-82.
[http://dx.doi.org/10.1128/JVI.02062-10] [PMID: 21068237]
[62]
Hoffmann M, Kleine-Weber H, Schroeder 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(2): 271-280.e8.
[http://dx.doi.org/10.1016/j.cell.2020.02.052] [PMID: 32142651]
[63]
Elmezayen AD, Al-Obaidi A. Şahin AT, Yelekçi K. Drug repurposing for coronavirus (COVID-19): in silico screening of known drugs against coronavirus 3CL hydrolase and protease enzymes. J Biomol Struct Dyn 2020; 39(8): 2980-92.
[PMID: 32306862]
[64]
Channappanavar R, Fett C, Mack M, Ten Eyck PP, Meyerholz DK, Perlman S. Sex-based differences in susceptibility to severe acute respiratory syndrome coronavirus infection. J Immunol 2017; 198(10): 4046-53.
[http://dx.doi.org/10.4049/jimmunol.1601896] [PMID: 28373583]
[65]
Sanders JM, Monogue ML, Jodlowski TZ, Cutrell JB. Pharmacologic treatments for coronavirus disease 2019 (COVID-19): A review. JAMA 2020; 323(18): 1824-36.
[PMID: 32282022]
[66]
Hu TY, Frieman M, Wolfram J. Insights from nanomedicine into chloroquine efficacy against COVID-19. Nat Nanotechnol 2020; 15(4): 247-9.
[http://dx.doi.org/10.1038/s41565-020-0674-9] [PMID: 32203437]
[67]
The race against COVID-19. Nat Nanotechnol 2020; 15(4): 239-40.
[http://dx.doi.org/10.1038/s41565-020-0680-y]
[68]
Nano Research for COVID-19. ACS Nano 2020.
[69]
Mahla RS. Stem cells applications in regenerative medicine and disease therapeutics. Int J Cell Biol 2016; 2016: 6940283.
[http://dx.doi.org/10.1155/2016/6940283]
[70]
Chrzanowski W, Kim SY, McClements L. Can stem cells beat COVID-19: advancing stem cells and extracellular vesicles towards mainstream medicine for lung injuries associated with SARS-CoV-2 infections. Front Bioeng Biotechnol 2020; 8: 554.
[http://dx.doi.org/10.3389/fbioe.2020.00554] [PMID: 32574317]
[71]
Bhattacharya J, Matthay MA. Regulation and repair of the alveolar-capillary barrier in acute lung injury. Annu Rev Physiol 2013; 75(1): 593-615.
[http://dx.doi.org/10.1146/annurev-physiol-030212-183756] [PMID: 23398155]
[72]
Rahmati M, Moosavi MA. Cytokine-targeted therapy in severely ill COVID-19 patients: options and cautions. EJMO 2020; 4(2): 179-80.
[http://dx.doi.org/10.14744/ejmo.2020.72142]
[73]
Ma Q, Pan W, Li R, et al. Liu Shen capsule shows antiviral and anti-inflammatory abilities against novel coronavirus SARS-CoV-2 via suppression of NF-κB signaling pathway. Pharmacol Res 2020; 158: 104850.
[http://dx.doi.org/10.1016/j.phrs.2020.104850] [PMID: 32360580]
[74]
Smith M, Smith JC. Repurposing therapeutics for COVID-19. Preprint 2020.
[75]
Minjee, Kim and young Bong, Kim. 2020. In silico synergistic drug repurposing for combating novel coronavirus (COVID- 19) outbreaks. Nature research. Status
[76]
Li X, Geng M, Peng Y, Meng L, Lu S. Molecular immune pathogenesis and diagnosis of COVID-19. Journal of Pharmaceutical Analysis 2020.
[77]
Mair-Jenkins J, Saavedra-Campos M, Baillie JK, et al. Convalescent plasma study group. The effectiveness of convalescent plasma and hyperimmune immunoglobulin for the treatment of severe acute respiratory infections of viral etiology: a systematic review and exploratory meta-analysis. J Infect Dis 2015; 211(1): 80-90.
[http://dx.doi.org/10.1093/infdis/jiu396] [PMID: 25030060]
[78]
Koenig KL. Identify-Isolate-Inform: A modified tool for initial detection and management of Middle East Respiratory Syndrome patients in the emergency department. West J Emerg Med 2015; 16(5): 619-24.
[http://dx.doi.org/10.5811/westjem.2015.7.27915] [PMID: 26587081]
[79]
Tian X, Li C, Huang A, et al. Potent binding of 2019 novel coronavirus spike protein by a SARS coronavirus-specific human monoclonal antibody. Emerging microbes infections 2020; 9(1): 382-5.
[http://dx.doi.org/10.1080/22221751.2020.1729069]
[80]
El-Aziz TMAJD. 2020. Stockand, Recent progress and challenges in drug development against COVID-19 coronavirus (SARS-CoV-2) – an update on the status. Infect Genet Evol 2020; 83: 109327.
[http://dx.doi.org/10.1016/j.meegid.2020.104327]
[81]
Malik YS, Sircar S, Bhat S, et al. Emerging novel coronavirus (2019-nCoV)-current scenario, evolutionary perspective based on genome analysis and recent developments. Vet Q 2020; 40(1): 68-76.
[http://dx.doi.org/10.1080/01652176.2020.1727993] [PMID: 32036774]
[82]
Di Gennaro F, Pizzol D, Marotta C, et al. Coronavirus diseases (COVID-19) current status and future perspectives: A narrative review. Int J Environ Res Public Health 2020; 17(8): 2690.
[http://dx.doi.org/10.3390/ijerph17082690] [PMID: 32295188]
[83]
Chhikara BS, Rathi B, Singh J, Poonam FNU. Corona virus SARS-CoV-2 disease COVID-19: Infection, prevention and clinical advances of the prospective chemical drug therapeutics. Chemical Biol Lett 2020; 7(1): 63-72.
[84]
McBride R, Fielding BC. The role of severe acute respiratory syndrome (SARS)-coronavirus accessory proteins in virus pathogenesis. Viruses 2012; 4(11): 2902-23.
[http://dx.doi.org/10.3390/v4112902] [PMID: 23202509]
[85]
Jones BA, Grace D, Kock R, et al. Zoonosis emergence linked to agricultural intensification and environmental change. Proc Natl Acad Sci USA 2013; 110(21): 8399-404.
[http://dx.doi.org/10.1073/pnas.1208059110] [PMID: 23671097]
[86]
Arbour N, Ekandé S, Côté G, et al. Persistent infection of human oligodendrocytic and neuroglial cell lines by human coronavirus 229E. J Virol 1999; 73(4): 3326-37.
[http://dx.doi.org/10.1128/JVI.73.4.3326-3337.1999] [PMID: 10074187]
[87]
The korean society of infectious diseases. Korean society for healthcare-associated infection control and prevention an unexpected outbreak of middle east respiratory syndrome coronavirus infection in the Republic of Korea. Infect Chemother 2015; 47: 120-2.
[88]
Jacomy H, Fragoso G, Almazan G, Mushynski WE, Talbot PJ. Human coronavirus OC43 infection induces chronic encephalitis leading to disabilities in BALB/C mice. Virology 2006; 349(2): 335-46.
[http://dx.doi.org/10.1016/j.virol.2006.01.049] [PMID: 16527322]
[89]
Kristian GAndersen, Andrew Rambaut, Ian Lipkin W, Edward C Holmes, Robert F Garry. The proximal origin of SARS-CoV-2. Nature Medicine 2020; 26: 450-2.