Unlocking Novel Drug Targets and Therapeutic Advancements Against RNA Viruses: Insights from HMPV and SARS-CoV-2

Year : 2025 | Volume : 15 | Issue : 03 | Page : 54 86
    By

    Anuja Dhilor,

  • Aanchal Verma,

  • Vibha Gupta,

  1. Research Scholar, Department of Biotechnology, Jaypee Institute of Information Technology, Noida, Sector 62, Uttar Pradesh, India
  2. Research Scholar, Department of Biotechnology, Jaypee Institute of Information Technology, Noida, Sector 62, Uttar Pradesh, India
  3. Associate Professor, Department of Biotechnology, Jaypee Institute of Information Technology, Noida, Sector 62, Uttar Pradesh, India

Abstract

Re-emerging RNA viruses pose a significant epidemiological welfare threat due to their high mutation rates, potential for zoonotic transmission, and capacity to cause widespread outbreaks such as Human Metapneumovirus (HMPV), Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), Influenza, etc. The rapid evolution and re-emergence of these viruses necessitate the development of novel drug targets and therapeutic strategies to combat existing and future outbreaks. This study focuses on structural as well as nonstructural targets of these RNA viruses, such as viral entry proteins, RNA-dependent RNA polymerases (RDRP), and other viral proteins involved in interaction with host factors and immune invasion for therapeutic interventions. For HMPV, fusion (F) protein is a key target for drug discovery which contains an RGD (Arg-Gly-Asp) motif, that binds RGD-binding integrins to mediate pH-independent membrane F. Masking this motif, using natural inhibitors, like ginkgolic acid, can block HMPV infection. SARS-CoV-2 treatments mostly target Spike protein and RDRP inhibitors. Natural product inhibitors of RDRP, such as epigallocatechin gallate and theaflavins mimic nucleotide substrates and disrupt viral RNA synthesis by causing premature termination or blocking further nucleotide addition. Specifically, SARS-Cov-2 RDRP forms a trimeric complex with Nsp7 and Nsp8 for its activity, and therefore, targeting these essential accessory proteins offers another strategy to inhibit viral genome duplication and prevent infection. This study highlights some novel strategies for developing effective therapeutics against HMPV and COVID-19, laying the groundwork for enhanced pandemic preparedness and response.

Keywords: RNA viruses, novel drug target/novel drug, F protein, RDRP, natural inhibitors

[This article belongs to Research and Reviews: A Journal of Microbiology and Virology ]

How to cite this article:
Anuja Dhilor, Aanchal Verma, Vibha Gupta. Unlocking Novel Drug Targets and Therapeutic Advancements Against RNA Viruses: Insights from HMPV and SARS-CoV-2. Research and Reviews: A Journal of Microbiology and Virology. 2025; 15(03):54-86.
How to cite this URL:
Anuja Dhilor, Aanchal Verma, Vibha Gupta. Unlocking Novel Drug Targets and Therapeutic Advancements Against RNA Viruses: Insights from HMPV and SARS-CoV-2. Research and Reviews: A Journal of Microbiology and Virology. 2025; 15(03):54-86. Available from: https://journals.stmjournals.com/rrjomv/article=2025/view=233173


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References

  1. Woolhouse ME, Gowtage-Sequeria S. Host range and emerging and reemerging pathogens. Emerg Infect Dis. 2005;11(12):1842–1847. doi: 10.3201/eid1112.050997.
  2. Paules CI, Marston HD, Fauci AS. Coronavirus infections—More than just the common cold. JAMA. 2020;323(8):707–708. doi: 10.1001/jama.2020.0757.
  3. Webster RG, Govorkova EA. Continuing challenges in influenza. Ann N Y Acad Sci. 2014;1323(1):115–139. doi: 10.1111/nyas.12462.
  4. Steinhauer DA, Holland JJ. Rapid evolution of RNA viruses. Annu Rev Microbiol. 1987;41:409–433. doi: 10.1146/annurev.mi.41.100187.002205.
  5. Smith EC, Denison MR. Coronaviruses as DNA Wannabes: A new model for the regulation of RNA virus genome duplication fidelity. PLoS Pathog. 2013;9(12):e1003760. doi: 10.1371/journal.ppat.1003760.
  6. Uyeki TM, Bernstein HH, Bradley JS, Englund JA, File TM, Fry AM, et al. Clinical practice guidelines by the Infectious Diseases Society of America: 2018 Update on diagnosis, treatment, chemoprophylaxis, and institutional outbreak management of seasonal influenza. Clin Infect Dis. 2019;68(6):e1–e47. doi: 10.1093/cid/ciz044.
  7. Feldmann H, Geisbert TW. Ebola haemorrhagic fever. Lancet. 2011;377(9768):849–862. doi: 10.1016/S0140-6736(10)60667-8.
  8. Falsey AR, Walsh EE. Respiratory syncytial virus infection in adults. Clin Microbiol Rev. 2000;13(3):371–384. doi: 10.1128/CMR.13.3.371.
  9. Shi T, McAllister DA, O’Brien KL, Simoes EAF, Madhi SA, Gessner BD, et al. Global, regional, and national disease burden estimates of acute lower respiratory infections due to respiratory syncytial virus in young children in 2015. Lancet. 2017;390(10098):946–958. doi: 10.1016/S0140-6736(17)30938-8.
  10. Zumla A, Hui DS, Perlman S. Middle East respiratory syndrome. Lancet. 2015;386(9997):995–1007. doi: 10.1016/S0140-6736(15)60454-8.
  11. van den Hoogen BG, de Jong JC, Groen J, Kuiken T, de Groot R, Fouchier RA, et al. A newly discovered human pneumovirus isolated from young children with respiratory tract disease. Nat Med. 2001;7(6):719–724. doi: 10.1038/89098.
  12. Schildgen O, Simon A, Williams J. New aspects on the respiratory syncytial virus (RSV) and human metapneumovirus (HMPV) in acute respiratory tract infections. Infection. 2007;35(5):321–325.
  13. Debiaggi M, Canducci F, Ceresola ER, Clementi M. The role of infections and coinfections with newly identified and emerging respiratory viruses in children. Virol J. 2012;9:247. doi: 10.1186/1743-422X-9-247.
  14. Zhu N, Zhang D, Wang W, Li X, Yang B, Song J, et al. A novel coronavirus from patients with pneumonia in China, 2019. N Engl J Med. 2020;382(8):727–733.
  15. Coronavirus disease (COVID-19) pandemic. World Health Organization. Accessed May 2025.
  16. Guan WJ, Ni ZY, Hu Y, Liang WH, Ou CQ, He JX, et al. Clinical characteristics of Coronavirus Disease 2019 in China. N Engl J Med. 2020;382(18):1708–1720.
  17. Mehta P, McAuley DF, Brown M, et al. COVID-19: Consider cytokine storm syndromes and immunosuppression. Lancet. 2020;395(10229):1033–1034. doi: 10.1016/S0140-6736(20)30628-0.
  18. Broor S, Bharaj P, Chahar HS. Human metapneumovirus: A new respiratory pathogen. J Biosci. 2008;33(4):483–493. doi: 10.1007/s12038-008-0067-y.
  19. Hamelin ME, Abed Y, Boivin G. Human metapneumovirus: A new player among respiratory viruses. Clin Infect Dis. 2004;38(7):983–990. doi: 10.1086/382536.
  20. Krammer F. SARS-CoV-2 vaccines in development. Nature. 2020;586(7830):516–527. doi: 10.1038/s41586-020-2798-3.
  21. Moore JP, Offit PA. SARS-CoV-2 vaccines and the growing threat of viral variants. JAMA. 2021;325(9):821–822. doi: 10.1001/jama.2021.1114.
  22. Schuster JE, Cox RG, Hastings AK, et al. A broadly neutralizing human monoclonal antibody against the fusion glycoprotein of human metapneumovirus. Proc Natl Acad Sci USA. 2015;112(8):2451–2456.
  23. Ulbrandt ND, Ji H, Patel NK, et al. Isolation and characterization of human monoclonal antibodies that potently neutralize human metapneumovirus. J Clin Invest. 2014;124(7):2908–2917.
  24. 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(2):281–292.e6. doi: 10.1016/j.cell.2020.02.058.
  25. 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(7807):215–220. doi: 10.1038/s41586-020-2180-5.
  26. Holmes EC, Goldstein SA, Rasmussen AL, Robertson DL, Crits-Christoph A, Wertheim JO, et al. The origins of SARS-CoV-2: A critical review. Cell. 2021;184(19):4848–4856. doi: 10.1016/j.cell.2021.08.017.
  27. Morens DM, Daszak P, Taubenberger JK. Escaping pandora’s box — Another novel coronavirus. N Engl J Med. 2020;382(14):1293–1295. doi: 10.1056/NEJMp2002106.
  28. Gao Y, Chen M, Zheng L, et al. The evolving epidemiology and transmission of COVID-19: A review of SARS-CoV-2 variants and subvariants. Semin Cancer Biol. 2025 May.
  29. Tian J, Jiang S, Wei X, et al. Immunological characteristics and vaccine development for SARS-CoV-2 and its variants. Vaccine. 2024;42(23):3387–3399.
  30. Saha MK, Sharma A, Ghosh P, et al. A comprehensive review on current knowledge of SARS-CoV-2 pathogenesis and therapeutics. Virol J. 2021;18.
  31. Shaikh M, Ghosh S, Kaur P, et al. Immunological response to SARS-CoV-2: From cells to tissues. Front Immunol. 2024;14.
  32. Zhang T, Ding L, Zheng J, et al. SARS-CoV-2 immune evasion mechanisms and vaccine design. Front Immunol. 2024;15.
  33. Bhatnagar A, Kumar R, Sinha S, et al. COVID-19 and immunopathogenesis: A comprehensive overview. Virol J. 2023;20.
  34. Khan H, Alvi FA, Yousaf M, et al. Overview of SARS-CoV-2 immunity and vaccine development. J Infect Public Health. 2024;17(1):1–7.
  35. Prompetchara JA, Ketloy C, Palaga T. Immune responses in COVID-19 and potential vaccines: Lessons learned from SARS and MERS epidemic. Asian Pac J Allergy Immunol. 2020;38(1):1–9. doi: 10.12932/AP-200220-0772.
  36. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395(10223):497–506. doi: 10.1016/S0140-6736(20)30183-5.
  37. Schildgen O, van den Hoogen B, Fouchier R, Tripp RA, Alvarez R, Manoha C, et al. Human Metapneumovirus: Lessons learned over the first decade. Clin Microbiol Rev. 2011;24(4):734–754. doi: 10.1128/CMR.00015-11.
  38. Piyaratna R, et al. Functional domains of the HMPV polymerase complex proteins. Virology. 2011;411(2):284–291.
  39. Papi A, et al. Restricted genome duplication of HMPV in dendritic cells. J Immunol. 2009;182(4):2364–2371.
  40. Bao X, et al. Suppression of innate immunity by HMPV M2-2 protein targeting MyD88. J Virol. 2013;87(22):12418–12428.
  41. Williams JV, et al. Viral load and kinetics in HMPV infection. J Infect Dis. 2004;189(9):1705–1710.
  42. Holmes EC, Goldstein SA, Rasmussen AL, et al. The origins of SARS-CoV-2: A critical review. Cell. 2021;184(19):4848–56.
  43. Biacchesi S, et al. Persistence of HMPV RNA in respiratory tissues. J Gen Virol. 2007;88(Pt 12):3302–3310.
  44. Laham FR, et al. Human metapneumovirus in young children with acute respiratory infection. J Infect Dis. 2004;190(7):1236–1240.
  45. Rutigliano JA, et al. Cytokine responses during HMPV infection. J Immunol. 2009;182(4):1993–2000.
  46. Falsey AR, et al. HMPV-induced Th2-type inflammation and mucus production. J Infect Dis. 2006;193(8):1143–1150.
  47. Skiadopoulos MH, et al. Immunomodulatory functions of HMPV SH and G proteins. Virology. 2007;358(1):90–100.
  48. Piedra PA, et al. HMPV disease burden in high-risk populations. Clin Infect Dis. 2017;65(5):852–859.
  49. Bao X, et al. Human metapneumovirus (HMPV) fusion and attachment proteins contribute to viral entry. J Virol. 2013;87(18):10042–10052.
  50. Smith TF, Reichert ML, Peterson LR. Coronavirus disease 2019: Epidemiology, virology, and clinical features. J Am Soc Cytopathol. 2020;9(6):666–673.
  51. Dhama M, Patel M, Yatoo S, et al. SARS-CoV-2 pathogenesis, immunological responses and potential therapeutic targets. J Infect Dev Ctries. 2021;15(1):5–12.
  52. Hasan SS, Capstick M, Ahmed D, et al. Immune evasion strategies of SARS-CoV-2: A systematic review. Clin Microbiol Rev. 2023;36(1):e00199–22.
  53. Boivin G, et al. Neurological complications associated with HMPV infection. Pediatr Infect Dis J. 2003;22(6):531–533.
  54. Walsh EE, et al. Seasonal patterns of HMPV infection. J Infect Dis. 2008;197(6):831–839.
  55. Hasan KA, Kumar S, Arif AS, et al. Molecular pathogenesis of SARS-CoV-2 and emerging therapeutic interventions. Virol J. 2021;18.
  56. Li Y, et al. Progress toward HMPV vaccines and antivirals. Vaccine. 2019;37(50):7144–7152.
  57. Hoffmann M, Kleine-Weber H, Schroeder S, Krüger N, Herrler T, Erichsen S, et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2. Cell. 2020;181(2):271–280.e8. doi: 10.1016/j.cell.2020.02.052.
  58. Peacock TP, Goldhill DH, Zhou J, Baillon L, Frise R, Swann OC, et al. The furin cleavage site in SARS-CoV-2 spike protein is required for transmission. Nat Microbiol. 2021;6(7):899–909. doi: 10.1038/s41564-021-00908-w.
  59. 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. 2021;12(1):2144. doi: 10.1038/s41467-021-22614-1.
  60. 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(21):11727–11734. doi: 10.1073/pnas.2003138117.
  61. Mons G, et al. Proteolytic activation of SARS-CoV-2 by TMPRSS2 and cathepsins. PLoS Pathog. 2020;16(3):e1008893.
  62. Harvey WT, Carabelli AM, Jackson B, Gupta RK, Thomson EC, Harrison EM, et al. SARS-CoV-2 variants, spike mutations, and immune escape. Nat Rev Microbiol. 2021;19(7):409–424. doi: 10.1038/s41579-021-00573-0.
  63. Arora P, et al. BA.2.86 variant spike mutations impact infectivity and neutralization. bioRxiv. 2023.
  64. Snijder EJ, et al. Coronavirus genome duplication organelles. Nat Rev Microbiol. 2020;18(9):579–597.
  65. Sola I, Almazán F, Zúñiga S, Enjuanes L. Continuous and discontinuous RNA synthesis in coronaviruses. Annu Rev Virol. 2015;2(1):265–288. doi: 10.1146/annurev-virology-100114-055218.
  66. Ghosh S, et al. SARS-CoV-2 assembly and trafficking via lysosomal pathway. Cell. 2020;183(6):1600–1610.
  67. Thorne LG, et al. SARS-CoV-2 evasion of innate immunity. Nat Microbiol. 2020;5(10):1404–1415.
  68. Kim D, Lee JY, Yang JS, Kim JW, Kim VN, Chang H. The architecture of the SARS-CoV-2 transcriptome. Cell. 2020;181(4):914–921. doi: 10.1016/j.cell.2020.04.011.
  69. Gao Y, Yan L, Huang Y, Liu F, Zhao Y, Cao L, et al. Structure of the RNA-dependent RNA polymerase from SARS-CoV-2. Science. 2020;368(6492):779–782. doi: 10.1126/science.abb7498.
  70. Sadler AJ, Williams BRG. PKR and OAS antiviral pathways. Nat Rev Immunol. 2008;8(10):689–700.
  71. Hackbart M, et al. Coronavirus Nsp15 limits dsRNA accumulation to evade immunity. J Virol. 2020;94(13):e02158–19.
  72. Park A, Iwasaki A. Type I and III interferons in antiviral defense. Nat Rev Immunol. 2020;20(7):466–481.
  73. Schubert K, Karousis ED, Jomaa A, Scaiola A, Echeverria B, Gurzeler LA, et al. SARS-CoV-2 Nsp1 binds ribosomal mRNA entry tunnel to inhibit translation. Nat Struct Mol Biol. 2020;27(10):959–966. doi: 10.1038/s41594-020-0511-8.
  74. Lu R, Zhao X, Li J, Niu P, Yang B, Wu H, et al. Genomic characterisation and epidemiology of 2019 novel coronavirus. Lancet. 2020;395(10224):565–574.
  75. V’Kovski P, Kratzel A, Steiner S, Stalder H, Thiel V. Coronavirus biology and genome duplication: Implications for SARS-CoV-2. Nat Rev Microbiol. 2021;19(3):155–170.
  76. Yin W, Mao C, Luan X, Shen DD, Shen Q, Su H, et al. Structural basis for inhibition of the RNA-dependent RNA polymerase from SARS-CoV-2 by Remdesivir. Science. 2020;368(6498):1499–1504. doi: 10.1126/science.abc1560.
  77. Hillen HS, Kokic G, Farnung L, Dienemann C, Tegunov D, Cramer P. Structure of replicating SARS-CoV-2 polymerase. Nature. 2020;584(7819):154–156. doi: 10.1038/s41586-020-2368-8.
  78. Zhang L, Lin D, Sun X, Curth U, Drosten C, Sauerhering L, et al. Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved α-ketoamide inhibitors. Science. 2020;368(6489):409–412. doi: 10.1126/science.abb3405.
  79. Klemm T, Ebert G, Calleja DJ, Allison CC, Richardson LW, Bernardini JP, et al. Mechanism and inhibition of the papain-like protease, PLpro, of SARS-CoV-2. EMBO J. 2020;39(18):e106275. doi: 10.15252/embj.2020106275.
  80. Gordon DE, Jang GM, Bouhaddou M, Xu J, Obernier K, White KM, et al. A SARS-CoV-2 protein interaction map reveals targets for drug repurposing. Nature. 2020;583(7816):459–468. doi: 10.1038/s41586-020-2286-9.
  81. Li JY, Liao CH, Wang Q, Tan YJ, Luo R, Qiu Y, et al. The ORF6, ORF8 and nucleocapsid proteins of SARS-CoV-2 inhibit type I interferon signaling pathway. Virus Res. 2020;286:198074. doi: 10.1016/j.virusres.2020.198074.
  82. Baños-Lara MDR, Piao B, Guerrero-Plata A. Differential mucosal immunological responses to human metapneumovirus infection in the upper and lower respiratory tract. Immunol Res. 2015;63(1–3):111–122.
  83. Collins PL, Fearns R, Graham BS. Respiratory syncytial virus: Virology, reverse genetics, and pathogenesis of disease. Curr Top Microbiol Immunol. 2013;372:3–38. doi: 10.1007/978-3-642-38919-1_1.
  84. Chang J, Braciale TJ. Respiratory syncytial virus infection suppresses lung CD8+ T-cell effector activity and alters the lung microenvironment. J Virol. 2002;76(20):10791–10798.
  85. Meng J, Stobart CC, Hotard AL, Moore ML. An overview of respiratory syncytial virus. PLoS Pathog. 2014;10(4):e1004016. doi: 10.1371/journal.ppat.1004016.
  86. Cox RG, Livesay SB, Johnson M, Ohi MD, Williams JV. The human metapneumovirus fusion protein mediates entry via an interaction with RGD-binding integrins. J Virol. 2012;86(22):12148–12160. doi: 10.1128/JVI.01133-12.
  87. Battles MB, McLellan JS. Respiratory syncytial virus entry and how to block it. Nat Rev Microbiol. 2019;17(4):233–245. doi: 10.1038/s41579-019-0149-x.
  88. Skiadopoulos MH, Biacchesi S, Buchholz UJ, Amaro-Carambot E, Surman SR, Collins PL, et al. Individual contributions of the human metapneumovirus attachment (G) and fusion (F) proteins to host cell binding and membrane fusion. J Virol. 2006;80(16):7796–7807.
  89. Mas V, Nair H, Campbell H, Melero JA, Williams JV. Structure and antigenicity of the pre-fusion F protein of human metapneumovirus. J Virol. 2013;87(2):1160–1170.
  90. Wen X, Krause JC, Leser GP, Cox RG, Lamb RA, Williams JV, et al. Structure of the human metapneumovirus fusion protein with neutralizing antibody identifies a pneumovirus antigenic site. Nat Struct Mol Biol. 2012;19(4):461–463. doi: 10.1038/nsmb.2250.
  91. Zumla A, Chan JF, Azhar EI, Hui DS, Yuen KY. Coronaviruses—drug discovery and therapeutic options. Nat Rev Drug Discov. 2016;15(5):327–347. doi: 10.1038/nrd.2015.37.
  92. McLellan JS, Yang Y, Graham BS, Kwong PD. Structure of respiratory syncytial virus fusion glycoprotein in the postfusion conformation reveals preservation of neutralizing epitopes. J Virol. 2011;85(15):7788–7796. doi: 10.1128/JVI.00555-11.
  93. Battles MB, Langedijk JP, Furmanova-Hollenstein P, Chaiwatpongsakorn S, Costello HM, Kwanten L, et al. Molecular mechanism of respiratory syncytial virus fusion inhibitors. Nat Chem Biol. 2016;12(2):87–93. doi: 10.1038/nchembio.1982.
  94. Chang A, Masante C, Buchholz UJ, Dutch RE. Human metapneumovirus (HMPV) F protein promotes membrane fusion by assembling into a six-helix bundle. J Virol. 2012;86(6):3230–3243. doi: 10.1128/JVI.06706-11.
  95. Huang K, Incognito L, Cheng X, Ulbrandt ND, Wu H. Respiratory syncytial virus-neutralizing monoclonal antibodies motavizumab and palivizumab inhibit fusion. J Virol. 2010;84(16):8132–8140. doi: 10.1128/JVI.02699-09.
  96. Guerrero-Plata A, Casola A, Garofalo RP. Human Metapneumovirus induces a profile of lung cytokines distinct from that of respiratory syncytial virus. J Virol. 2005;79(23):14992–14997. doi: 10.1128/JVI.79.23.14992-14997.2005.
  97. Schindler D, Zhang Q, Pulendran B. Innate immunity and human metapneumovirus: advances in vaccine design. Curr Opin Immunol. 2020;65:90–97.
  98. Schildgen O, Simon A, Williams J. Animal models for human metapneumovirus (HMPV) infections. Vet Res. 2007;38(1):117–126. doi: 10.1051/vetres:2006051.
  99. Swanson KA, Settembre EC, Shaw CA, Dey AK, Rappuoli R, Mandl CW, et al. Structural basis for immunization with postfusion respiratory syncytial virus fusion F protein to elicit high-affinity neutralizing antibodies. Proc Natl Acad Sci U S A. 2011;108(23):9619–9624. doi: 10.1073/pnas.1106536108.
  100. Tang RS, MacPhail M, Schickli JH, Kaur J, Robinson C, Lawlor H, et al. Parainfluenza virus type 3-derived chimeric human metapneumovirus live attenuated vaccine candidates. J Virol. 2003;77(17):9824–9832.
  101. Tang RS, Spaete RR, MacPhail M, Schickli JH, Dubovsky F, Kaur J, et al. Parainfluenza virus type 3-derived chimeric human metapneumovirus live attenuated vaccine candidates. Vaccine. 2005;23(49):5073–5082.
  102. Chang A, Masante C, Buchholz UJ, Dutch RE. Human metapneumovirus (HMPV) binding and infection are mediated by interactions between the HMPV fusion protein and heparan sulfate. J Virol. 2012;86(6):3230–3243. doi: 10.1128/JVI.06706-11.
  103. Piyaratna R, Tollefson SJ, Williams JV. Genomic analysis of four human metapneumovirus prototypes. Virus Res. 2011;160(1–2):200–205. doi: 10.1016/j.virusres.2011.06.014.
  104. Wen X, Krause JC, Leser GP, Cox RG, Kim JI, Yoon S, et al. Structure of the human metapneumovirus fusion protein with neutralizing antibody binding sites. Proc Natl Acad Sci U S A. 2012;109(35):14301–14306.
  105. Wu F, Zhao S, Yu B, Chen Y-M, Wang W, Song Z-G, et al. A new coronavirus associated with human respiratory disease in China. Nature. 2020;579(7798):265–269. doi: 10.1038/s41586-020-2008-3.
  106. Wu A, Peng Y, Huang B, Ding X, Wang X, Niu P, et al. Genome composition and divergence of the novel coronavirus (2019-nCoV) originating in China. Cell Host Microbe. 2020;27(3):325–328. doi: 10.1016/j.chom.2020.02.001.
  107. Kim D, Lee JY, Yang JS, et al. The architecture of SARS-CoV-2 transcriptome. Cell. 2020;181(4):914–921.e10. doi: 10.1016/j.cell.2020.04.011.
  108. Snijder EJ, Decroly E, Ziebuhr J. The nonstructural proteins directing coronavirus RNA synthesis and processing. Adv Virus Res. 2016;96:59–126. doi: 10.1016/bs.aivir.2016.08.008.
  109. Subissi L, Imbert I, Ferron F, Collet A, Coutard B, Decroly E, et al. SARS-CoV ORF1b codes for nonstructural proteins 12–16: Replicative enzymes as antiviral targets. Antiviral Res. 2014;101:122–130. doi: 10.1016/j.antiviral.2013.11.006.
  110. Shannon A, Le NT, Selisko B, Eydoux C, Alvarez K, Guillemot J-C, et al. Remdesivir and SARS-CoV-2: structural requirements at both Nsp12 RDRP and Nsp14 exonuclease active-sites. Antiviral Res. 2020;178:104793. doi: 10.1016/j.antiviral.2020.104793.
  111. Ogando NS, Ferron F, Decroly E, et al. The curious case of the nidovirus exoribonuclease: Its role in RNA synthesis and genome duplication fidelity. Viruses. 2019;11(8):733.
  112. Kirchdoerfer RN, Ward AB. Structure of the SARS-CoV Nsp12 polymerase bound to Nsp7 and Nsp8 co-factors. Nat Commun. 2019;10(1):2342.
  113. Zhai Y, Sun F, Li X, et al. Insights into SARS-CoV-2 RNA synthesis machinery. Cell Res. 2020;30(8):703–706.
  114. Wang Q, Wu J, Wang H, Gao Y, Liu Q, Mu A, et al. Structural basis for RNA replication by the SARS-CoV-2 polymerase. Cell. 2020;182(2):417–428.e13. doi: 10.1016/j.cell.2020.05.034.
  115. Madhugiri R, Fricke M, Marz M, Ziebuhr J. Coronavirus cis-acting RNA elements. Adv Virus Res. 2016;96:127–163. doi: 10.1016/bs.aivir.2016.08.007.
  116. Knoops K, Kikkert M, van den Worm SHE, Zevenhoven-Dobbe JC, van der Meer Y, Koster AJ, et al. SARS-coronavirus genome duplication is supported by a reticulovesicular network of modified endoplasmic reticulum. PLoS Biol. 2008;6(9):e226. doi: 10.1371/journal.pbio.0060226.
  117. Robson F, Khan KS, Le TK, Paris C, Demirbag S, Barfuss P, et al. Coronavirus RNA proofreading: Molecular basis and therapeutic targeting. Mol Cell. 2020;79(5):710–727. doi: 10.1016/j.molcel.2020.07.027.
  118. Eastman RT, Roth JS, Brimacombe KR, Simeonov A, Shen M, Patnaik S, et al. Remdesivir: A review of its discovery and development leading to emergency use authorization for treatment of COVID-19. ACS Cent Sci. 2020;6(5):672–683. doi: 10.1021/acscentsci.0c00489.
  119. Kabinger F, Stiller C, Schmitzová J, Dienemann C, Kokic G, Hillen HS, et al. Mechanism of molnupiravir-induced SARS-CoV-2 mutagenesis. Nat Struct Mol Biol. 2021;28(9):740–746. doi: 10.1038/s41594-021-00651-0.
  120. Painter WP, Holman W, Bush JA, Almazedi F, Malik H, Eraut NCJ, et al. Human safety, tolerability, and pharmacokinetics of molnupiravir, a novel broad-spectrum oral antiviral agent with activity against SARS-CoV-2. Antimicrob Agents Chemother. 2021;65(5):e02428–20. doi: 10.1128/AAC.02428-20.
  121. Shannon A, Selisko B, Le NT, Huchting J, Touret F, Piorkowski G, et al. Rapid incorporation of Favipiravir by the fast and permissive viral RNA polymerase complex results in SARS-CoV-2 lethal mutagenesis. Nat Commun. 2020;11(1):4682. doi: 10.1038/s41467-020-18463-z.
  122. Kokic G, Hillen HS, Tegunov D, Dienemann C, Seitz F, Schmitzova J, et al. Mechanism of SARS-CoV-2 polymerase stalling by remdesivir. Nat Commun. 2021;12:279. doi: 10.1038/s41467-020-20542-0.
  123. Ferron F, Subissi L, De Morais ATS, Le NTT, Sevajol M, Gluais L, et al. Structural and molecular basis of mismatch correction and ribavirin excision from coronavirus RNA. Proc Natl Acad Sci U S A. 2018;115(2):E162–E171. doi: 10.1073/pnas.1718806115.
  124. Agostini ML, Andres EL, Sims AC, Graham RL, Sheahan TP, Lu X, et al. Coronavirus susceptibility to the antiviral remdesivir (GS-5734) is mediated by the viral polymerase and the proofreading exoribonuclease. mBio. 2018;9(2):e00221–18. doi: 10.1128/mBio.00221-18.
  125. Gordon CJ, Tchesnokov EP, Feng JY, Porter DP, Götte M. The antiviral compound remdesivir potently inhibits RNA-dependent RNA polymerase from Middle East respiratory syndrome coronavirus. J Biol Chem. 2020;295(15):4773–4779. doi: 10.1074/jbc.AC120.013056.
  126. Li Z, Tomlinson AC, Wong AH, et al. The human coronavirus HCoV-229E nonstructural protein Nsp8 is a dimer and the Nsp7–Nsp8 complex forms a hexadecamer. J Mol Biol. 2020;432(3):807–821.
  127. Eydoux C, Fattorini V, Shannon A, Le T-T-N, Didier B, Canard B, et al. A fluorescence-based high throughput-screening assay for the SARS-CoV RNA synthesis complex. Anal Bioanal Chem. 2021;413(1):51–62. doi: 10.1016/j.jviromet.2020.114013.
  128. Ton AT, Gentile F, Hsing M, Ban F, Cherkasov A. Rapid identification of potential inhibitors of SARS-CoV-2 main protease by deep docking of 1.3 billion compounds. Mol Inform. 2020;39(8):e2000028. doi: 10.1002/minf.202000028.
  129. Duan X, Liu X, He L, et al. Antiviral combination therapy: A strategy to overcome drug resistance of influenza A virus and coronavirus. Acta Pharm Sin B. 2022;12(9):3329–3343.
  130. Collins PL, Karron RA. Respiratory syncytial virus and metapneumovirus. In: Fields Virology. 6th ed. Philadelphia: Lippincott Williams & Wilkins; 2013. p. 1086–1123.
  131. Cox RG, Williams JV. Human Metapneumovirus: Epidemiology, Pathogenesis, and Clinical Manifestations. J Clin Virol. 2013;58(4):301–7.
  132. Noton SL, Fearns R. The initiation and regulation of paramyxovirus transcription and replication. Virology. 2015;479–480:545–54.
  133. Liang B, Li Z, Jenni S, Rahmeh AA, Morin BM, Grant T, et al. Structure of the L Protein of Vesicular Stomatitis Virus from Electron Cryomicroscopy. Cell. 2015;162(2):314–27.
  134. Ogino T, Green TJ. RNA synthesis and capping by nonsegmented negative strand RNA viral polymerases: Lessons from a prototypic virus. Front Microbiol. 2019;10:1490.
  135. Ogino T, Banerjee AK. An RNA-dependent RNA polymerase of respiratory syncytial virus performs both mRNA capping and cap methylation. PLoS Pathog. 2011;7(8):e1001248.
  136. Gilman MSA, Liu C, Fung A, Behera I, Jordan P, Rigaux P, et al. Structure of the respiratory syncytial virus polymerase complex. Proc Natl Acad Sci USA. 2019;116(42):19901–7.
  137. Buchholz UJ, Biacchesi S, Pham QN, Tran KC, Yang L, Luongo CL, et al. Deletion of M2-1 and M2-2 genes from human metapneumovirus reveals their essential roles in RNA synthesis and virus replication. J Virol. 2005;79(10):6588–97.
  138. R. Braun, S. L. Noton, E. L. Blanchard, A. Shareef, P. J. Santangelo, W. E. Johnson, and R. Fearns, “Respiratory syncytial virus M2-1 protein associates non-specifically with viral messenger RNA and with specific cellular messenger RNA transcripts,” PLoS Pathogens, vol. 17, no. 5, e1009589, May 2021, doi: 10.1371/journal.ppat.1009589.
  139. Züst R, Cervantes-Barragán L, Kuri T, Blakqori G, Weber F, Ludewig B, et al. Ribose 2′-O-methylation provides a molecular signature for the distinction of self and non-self mRNA. Nature Immunol. 2011;12(2):137–43.
  140. Cartee TL, Wertz GW. Respiratory syncytial virus M2-1 protein requires phosphorylation for efficient function and nucleocapsid binding. J Virol. 2001;75(24):12188–97. 37© STM Journals 2021. All Rights Reserved
  141. Hardy RW, Wertz GW. The product of the respiratory syncytial virus M2 gene is a transcription elongation factor. J Virol. 1998;72(6):5208–19.
  142. Biacchesi S, Pham QN, Skiadopoulos MH, Murphy BR, Collins PL, Buchholz UJ. Infection of nonhuman primates with recombinant human metapneumovirus lacking the SH, G, or M2-2 protein categorizes each as a nonessential accessory protein and identifies vaccine candidates. J Virol. 2005;79(19):12608–13.
  143. Spann KM, Tran KC, Collins PL. Effects of nonstructural proteins NS1 and NS2 of human metapneumovirus on interferon responses of human dendritic cells. J Virol. 2005;79(13):8771–9.
  144. Murphy SK, Parks GD. RNA replication for paramyxoviruses. Methods Mol Biol. 2016;1349:153–68.
  145. Deval J, Symons JA, Beigelman L. Inhibition of viral RNA polymerases by nucleoside and nucleotide analogs: therapeutic implications for RNA virus infections. Antiviral Res. 2014;119:96–110.
  146. Crotty S, Cameron CE, Andino R. RNA virus error catastrophe: Direct molecular test by using ribavirin. Proc Natl Acad Sci USA. 2001;98(12):6895–900.
  147. Finke S, Conzelmann KK. Replication strategies of rabies virus . J Vet Med B. 2005;52(7–8):287–93.
  148. Cai Y, Zhang J, Xiao T, et al. “Distinct conformational states of SARS-CoV-2 spike protein.” Science. 2020;369(6511):1586-1592.
  149. Johnson BA, Xie X, Bailey AL, et al. “Loss of furin cleavage site attenuates SARS-CoV-2 pathogenesis.” Nature. 2021;591(7849):293-299.
  150. Braun E, Sauter D. “Furin-mediated protein processing in infectious diseases and cancer.” Clin Transl Immunology. 2019;8(8):e1073.
  151. Mészáros B, Erdős G, Dosztányi Z. “Short linear motif candidates in the cell entry system used by SARS-CoV-2 and their potential therapeutic implications.” Sci Signal. 2021;14(672):eabd0334.
  152. Hoffmann M, Kleine-Weber H, Pöhlmann 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(4):779-784.e5.
  153. Grant OC, Montgomery D, Ito K, Woods RJ. “Analysis of the SARS-CoV-2 spike protein glycan shield reveals implications for immune recognition.” Sci Rep. 2020;10(1):14991.
  154. Gong Y, Qin S, Dai L, Tian Z. “The glycosylation in SARS-CoV-2 and its receptor ACE2.” Signal Transduct Target Ther. 2021;6(1):396.
  155. Lee JS, Shin EC. The type I interferon response in COVID-19: implications for treatment. Nat Rev Immunol.2020;20(10):585–6.
  156. Corti D, et al. Tackling COVID-19 with neutralizing monoclonal antibodies. Cell. 2021;184(12):3086108.
  157. Han Y, Král P. Computational design of ACE2-based peptide inhibitors of SARS-CoV-2. ACS Nano. 2020;14(4):5143–7.
  158. Koenig PA, et al. Structure-guided multivalent nanobodies block SARS-CoV-2 infection and suppress mutational escape. Science. 2021;371(6530)
Regular Issue Subscription Review Article
Volume 15
Issue 03
Received 22/05/2025
Accepted 06/08/2025
Published 08/08/2025
Publication Time 78 Days
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