DOI QR코드

DOI QR Code

Advancements in Antiviral Drug Development: Comprehensive Insights into Design Strategies and Mechanisms Targeting Key Viral Proteins

  • Wang Hangyu (Key Laboratory of Immune Microenvironment and Inflammatory Disease Research in Universities of Shandong Province, School of Basic Medical Sciences, Shandong Second Medical University) ;
  • Li Panpan (Key Laboratory of Immune Microenvironment and Inflammatory Disease Research in Universities of Shandong Province, School of Basic Medical Sciences, Shandong Second Medical University) ;
  • Shen Jie (School of Medical Laboratory, Shandong Second Medical University) ;
  • Wang Hongyan (Key Laboratory of Immune Microenvironment and Inflammatory Disease Research in Universities of Shandong Province, School of Basic Medical Sciences, Shandong Second Medical University) ;
  • Wei Linmiao (Key Laboratory of Immune Microenvironment and Inflammatory Disease Research in Universities of Shandong Province, School of Basic Medical Sciences, Shandong Second Medical University) ;
  • Han Kangning (Key Laboratory of Immune Microenvironment and Inflammatory Disease Research in Universities of Shandong Province, School of Basic Medical Sciences, Shandong Second Medical University) ;
  • Shi Yichen (School of Stomatology, Shandong Second Medical University) ;
  • Wang Shuai (Department of Rheumatology and Immunology, The Affiliated Hospital of Inner Mongolia Medical University) ;
  • Wang Cheng (Department of Rheumatology and Immunology, The Affiliated Hospital of Inner Mongolia Medical University)
  • Received : 2024.03.07
  • Accepted : 2024.04.09
  • Published : 2024.07.28

Abstract

Viral infectious diseases have always been a threat to human survival and quality of life, impeding the stability and progress of human society. As such, researchers have persistently focused on developing highly efficient, low-toxicity antiviral drugs, whether for acute or chronic infectious diseases. This article presents a comprehensive review of the design concepts behind virus-targeted drugs, examined through the lens of antiviral drug mechanisms. The intention is to provide a reference for the development of new, virus-targeted antiviral drugs and guide their clinical usage.

Keywords

Acknowledgement

This work was supported by grants from the Natural Science Foundation of Shandong Province (ZR2022QH165, ZR2022QH147, ZR2022MH172), Development Programme for Young Innovation Teams in Shandong Higher Education Institutions (2023KJ254), Natural Science Foundation of Inner Mongolia Autonomous Region (2023QN08002), Inner Mongolia Medical University General Project (YKD2022MS005), Inner Mongolia Autonomous Region High-Level Talent Research Support Fund (186), and Inner Mongolia Autonomous Region Talent Development Fund (2023).

References

  1. Beyrer C, Pozniak A. 2017. HIV drug resistance - an emerging threat to epidemic control. N. Engl. J. Med. 377: 1605-1607. 
  2. Kormuth KA, Lakdawala SS. 2020. Emerging antiviral resistance. Nat. Microbiol. 5: 4-5. 
  3. Zhang H, Quadeer AA, McKay MR. 2023. Direct-acting antiviral resistance of Hepatitis C virus is promoted by epistasis. Nat. Commun. 14: 7457. 
  4. Zou G, Cao S, Gao Z, Yie J, Wu JZ. 2024. Current state and challenges in respiratory syncytial virus drug discovery and development. Antiviral Res. 221: 105791. 
  5. Wei Y, Liu H, Hu D, He Q, Yao C, Li H, et al. 2023. Recent advances in enterovirus A71 infection and antiviral agents. Lab. Invest. 104: 100298. 
  6. Mahajan S, Choudhary S, Kumar P, Tomar S. 2021. Antiviral strategies targeting host factors and mechanisms obliging +ssRNA viral pathogens. Bioorg. Med. Chem. 46: 116356. 
  7. Xiao T, Cai Y, Chen B. 2021. HIV-1 entry and membrane fusion inhibitors. Viruses 13: 735. 
  8. Segal-Maurer S, DeJesus E, Stellbrink HJ, Castagna A, Richmond GJ, Sinclair GI, et al. 2022. Capsid inhibition with lenacapavir in multidrug-resistant HIV-1 infection. N. Engl. J. Med. 386: 1793-1803. 
  9. Kang JX, Zhao GK, Yang XM, Huang MX, Hui WQ, Zeng R, et al. 2023. Recent advances on dual inhibitors targeting HIV reverse transcriptase associated polymerase and ribonuclease H. Eur. J. Med. Chem. 250: 115196. 
  10. Boby ML, Fearon D, Ferla M, Filep M, Koekemoer L, Robinson MC, et al. 2023. Open science discovery of potent noncovalent SARS-CoV-2 main protease inhibitors. Science 382: eabo7201. 
  11. Lee C. 2019. CRISPR/Cas9-based antiviral strategy: current status and the potential challenge. Molecules (Basel, Switzerland) 24: 1349. 
  12. Nguyen H, Wilson H, Jayakumar S, Kulkarni V, Kulkarni S. 2021. Efficient inhibition of HIV using CRISPR/Cas13d nuclease system. Viruses 13: 1850. 
  13. Leal ES, Pascual MJ, Adler NS, Arrupe N, Merwaiss F, Giordano L, et al. 2024. Unveiling tetrahydroquinolines as promising BVDV entry inhibitors: targeting the envelope protein. Virology 590: 109968. 
  14. Bai Y, Jones JC, Wong SS, Zanin M. 2021. Antivirals targeting the surface glycoproteins of influenza virus: mechanisms of action and resistance. Viruses 13: 624. 
  15. Zhang Q, Liang T, Nandakumar KS, Liu S. 2021. Emerging and state of the art hemagglutinin-targeted influenza virus inhibitors. Exp. Opin. Pharmacother. 22: 715-728. 
  16. Kadam RU, Wilson IA. 2017. Structural basis of influenza virus fusion inhibition by the antiviral drug arbidol. Proc. Natl. Acad. Sci. USA 114: 206-214. 
  17. Badani H, Garry RF, Wilson RB, Wimley WC. 2011. Mechanism and action of flufirvitide, a peptide inhibitor of influenza virus infection. Biophys. J. 100: 216a. 
  18. Han X, Si LL, Shi YY, Fan ZB, Wang SX, Tian ZY, et al. 2017. Synthesis and in vitro anti-influenza virus evaluation of novel sialic acid (C-5 and C-9)-pentacyclic triterpene derivatives. Molecules 22: 1018. 
  19. Tsuji M, Sriwilaijaroen N, Inoue H, Miki K, Kinoshita K, Koyama K, et al. 2018. Synthesis and anti-influenza virus evaluation of triterpene-sialic acid conjugates. Bioorg. Med. Chem. 26: 17-24. 
  20. Sautto GA, Ross TM. 2019. Hemagglutinin consensus-based prophylactic approaches to overcome influenza virus diversity. Vet. Italiana 55: 195-201. 
  21. Wu NC, Wilson IA. 2020. Influenza hemagglutinin structures and antibody recognition. Cold Spring Harb. Perspect. Med. 10: a038778. 
  22. McAuley JL, Gilbertson BP, Trifkovic S, Brown LE, McKimm-Breschkin JL. 2019. Influenza virus neuraminidase structure and functions. Front. Microbiol. 10: 39. 
  23. Gong J, Xu W, Zhang J. 2007. Structure and functions of influenza virus neuraminidase. Curr. Med. Chem. 14: 113-122. 
  24. van der Vries E, Schutten M, Fraaij P, Boucher C, Osterhaus A. 2013. Influenza virus resistance to antiviral therapy. Adv. Pharmacol. 67: 217-246. 
  25. Han J, Perez J, Schafer A, Cheng H, Peet N, Rong L, et al. 2018. Influenza virus: small molecule therapeutics and mechanisms of antiviral resistance. Curr. Med. Chem. 25: 5115-5127. 
  26. Lampejo T. 2020. Influenza and antiviral resistance: an overview. Eur. J. Clin. Microbiol. Infect. Dis. 39: 1201-1208. 
  27. Yang H, Rao Z. 2021. Structural biology of SARS-CoV-2 and implications for therapeutic development. Nat. Rev. Microbiol. 19: 685-700. 
  28. Cai Y, Zhang J, Xiao T, Peng H, Sterling SM, Walsh RM Jr., et al. 2020. Distinct conformational states of SARS-CoV-2 spike protein. Science 369: 1586-1592. 
  29. Wang Q, Zhang Y, Wu L, Niu S, Song C, Zhang Z, et al. 2020. Structural and functional basis of SARS-CoV-2 entry by using human ACE2. Cell 181: 894-904 e899. 
  30. Yan R, Zhang Y, Li Y, Xia L, Guo Y, Zhou Q. 2020. Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2. Science 367: 1444-1448. 
  31. Vankadari N. 2020. Arbidol: a potential antiviral drug for the treatment of SARS-CoV-2 by blocking trimerization of the spike glycoprotein. Int. J. Antimicrob. Agents 56: 105998. 
  32. Padhi AK, Seal A, Khan JM, Ahamed M, Tripathi T. 2021. Unraveling the mechanism of arbidol binding and inhibition of SARS-CoV-2: insights from atomistic simulations. Eur. J. Pharmacol. 894: 173836. 
  33. Barnes CO, West AP Jr., Huey-Tubman KE, Hoffmann MAG, Sharaf NG, Hoffman PR, et al. 2020. Structures of human antibodies bound to SARS-CoV-2 spike reveal common epitopes and recurrent features of antibodies. Cell 182: 828-842 e816. 
  34. Shi R, Shan C, Duan X, Chen Z, Liu P, Song J, et al. 2020. A human neutralizing antibody targets the receptor-binding site of SARS-CoV-2. Nature 584: 120-124. 
  35. Yuan M, Liu H, Wu NC, Lee CD, Zhu X, Zhao F, et al. 2020. Structural basis of a shared antibody response to SARS-CoV-2. Science 369: 1119-1123. 
  36. Chan DC, Fass D, Berger JM, Kim PS. 1997. Core structure of gp41 from the HIV envelope glycoprotein. Cell 89: 263-273. 
  37. Weissenhorn W, Dessen A, Harrison SC, Skehel JJ, Wiley DC. 1997. Atomic structure of the ectodomain from HIV-1 gp41. Nature 387: 426-430. 
  38. Lai YT. 2021. Small molecule HIV-1 attachment inhibitors: discovery, mode of action and structural basis of inhibition. Viruses 13: 843. 
  39. Dove A. 2001. New class of HIV drugs shows promise. Nat. Med. 7: 1265. 
  40. Kilby JM, Lalezari JP, Eron JJ, Carlson M, Cohen C, Arduino RC, et al. 2002. The safety, plasma pharmacokinetics, and antiviral activity of subcutaneous enfuvirtide (T-20), a peptide inhibitor of gp41-mediated virus fusion, in HIV-infected adults. AIDS Res. Human Retroviruses 18: 685-693. 
  41. Aiken C, Rousso I. 2021. The HIV-1 capsid and reverse transcription. Retrovirology 18: 29. 
  42. Dvory-Sobol H, Shaik N, Callebaut C, Rhee MS. 2022. Lenacapavir: a first-in-class HIV-1 capsid inhibitor. Curr. Opin. HIV AIDS 17: 15-21. 
  43. Thenin-Houssier S, Valente ST. 2016. HIV-1 capsid inhibitors as antiretroviral agents. Curr. HIV Res. 14: 270-282. 
  44. Kuduk SD, Stoops B, Lam AM, Espiritu C, Vogel R, Lau V, et al. 2021. Oxadiazepinone HBV capsid assembly modulators. Bioorg. Med. Chem. Lett. 52: 128353. 
  45. Kim W, Kang JA, Park M, Jeong PH, Kim YJ, Cho Y, et al. 2021. Discovery of novel pyrimidine-based capsid assembly modulators as potent anti-HBV agents. J. Med. Chem. 64: 5500-5518. 
  46. Toyama M, Sakakibara N, Takeda M, Okamoto M, Watashi K, Wakita T, et al. 2019. Pyrimidotriazine derivatives as selective inhibitors of HBV capsid assembly. Virus Res. 271: 197677. 
  47. Qiu Z, Lin X, Zhou M, Liu Y, Zhu W, Chen W, et al. 2016. Design and synthesis of orally bioavailable 4-Methyl heteroaryldihydropyrimidine based hepatitis B virus (HBV) capsid inhibitors. J. Med. Chem. 59: 7651-7666. 
  48. Giacchello I, Musumeci F, D'Agostino I, Greco C, Grossi G, Schenone S. 2021. Insights into RNA-dependent RNA polymerase inhibitors as antiinfluenza virus agents. Curr. Med. Chem. 28: 1068-1090. 
  49. Massari S, Desantis J, Nizi MG, Cecchetti V, Tabarrini O. 2021. Inhibition of influenza virus polymerase by interfering with its protein-protein interactions. ACS Infect. Dis. 7: 1332-1350. 
  50. Yuan S, Wen L, Zhou J. 2018. Inhibitors of influenza A virus polymerase. ACS Infect. Dis. 4: 218-223. 
  51. Furuta Y, Gowen BB, Takahashi K, Shiraki K, Smee DF, Barnard DL. 2013. Favipiravir (T-705), a novel viral RNA polymerase inhibitor. Antiviral Res. 100: 446-454. 
  52. Furuta Y, Komeno T, Nakamura T. 2017. Favipiravir (T-705), a broad spectrum inhibitor of viral RNA polymerase. Proc. Japan Acad. Ser. B Phys. Biol. Sci. 93: 449-463. 
  53. Shiraki K, Daikoku T. 2020. Favipiravir, an anti-influenza drug against life-threatening RNA virus infections. Pharmacol. Ther. 209: 107512. 
  54. Mifsud EJ, Hayden FG, Hurt AC. 2019. Antivirals targeting the polymerase complex of influenza viruses. Antiviral Res. 169: 104545. 
  55. Patel MC, Chesnokov A, Jones J, Mishin VP, De La Cruz JA, Nguyen HT, et al. 2021. Susceptibility of widely diverse influenza a viruses to PB2 polymerase inhibitor pimodivir. Antiviral Res. 188: 105035. 
  56. Takashita E. 2021. Influenza polymerase inhibitors: mechanisms of action and resistance. Cold Spring Harb. Perspect. Med. 11: a038687. 
  57. Gao Y, Yan L, Huang Y, Liu F, Zhao Y, Cao L, et al. 2020. Structure of the RNA-dependent RNA polymerase from COVID-19 virus. Science 368: 779-782. 
  58. Chen J, Malone B, Llewellyn E, Grasso M, Shelton PMM, Olinares PDB, et al. 2020. Structural basis for helicase-polymerase coupling in the SARS-CoV-2 replication-transcription complex. Cell 182: 1560-1573 e1513. 
  59. Wang Q, Wu J, Wang H, Gao Y, Liu Q, Mu A, et al. 2020. Structural basis for RNA replication by the SARS-CoV-2 polymerase. Cell 182: 417-428.e413. 
  60. Brussow H. 2021. Clinical trials with antiviral drugs against COVID-19: some progress and many shattered hopes. Environ. Microbiol. 23: 6364-6376. 
  61. Peng F, Yuan H, Wu S, Zhou Y. 2021. Recent advances on drugs and vaccines for COVID-19. Inquiry 58: 469580211055630. 
  62. Wu J, Wang H, Liu Q, Li R, Gao Y, Fang X, et al. 2021. Remdesivir overcomes the S861 roadblock in SARS-CoV-2 polymerase elongation complex. Cell Rep. 37: 109882. 
  63. Yin W, Luan X, Li Z, Zhou Z, Wang Q, Gao M, et al. 2021. Structural basis for inhibition of the SARS-CoV-2 RNA polymerase by suramin. Nat. Struct. Mol. Biol. 28: 319-325. 
  64. De Clercq E. 2021. 1984-discovery of the first anti-HIV drug, suramin. Viruses 13: 1646. 
  65. Havens JP, Podany AT, Scarsi KK, Fletcher CV. 2020. Clinical pharmacokinetics and pharmacodynamics of etravirine: an updated review. Clin. Pharmacokinet. 59: 137-154. 
  66. Schrijvers R. 2013. Etravirine for the treatment of HIV/AIDS. Exp. Opin. Pharmacother. 14: 1087-1096. 
  67. Soriano V, Barreiro P, Cachay E, Kottilil S, Fernandez-Montero JV, de Mendoza C. 2020. Advances in hepatitis B therapeutics. Ther. Adv. Infect. Dis. 7: 2049936120965027. 
  68. Gao J, Ju C. 2017. Research progress on the direct antiviral drugs for hepatitis C virus. Biosci. Ttrends 11: 41-45. 
  69. Zeuzem S. 2017. Treatment options in hepatitis C. Deutsches Arzteblatt International. 114: 11-21. 
  70. Ghosh AK, Markad SB, Robinson WL. 2021. The chiron approach to (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol, a key subunit of HIV-1 protease inhibitor drug, darunavir. J. Organic Chem. 86: 1216-1222. 
  71. Llibre JM, Imaz A, Clotet B. 2013. From TMC114 to darunavir: five years of data on efficacy. AIDS Rev. 15: 112-121. 
  72. Paton NI, Musaazi J, Kityo C, Walimbwa S, Hoppe A, Balyegisawa A, et al. 2021. Dolutegravir or darunavir in combination with zidovudine or tenofovir to treat HIV. N. Eng. J. Med. 385: 330-341. 
  73. Sarkar A, Mandal K. 2021. Repurposing an antiviral drug against SARS-CoV-2 main protease. Angew. Chem. Int. Ed Engl. 60: 23492-23494. 
  74. Dai W, Zhang B, Jiang XM, Su H, Li J, Zhao Y, et al. 2020. Structure-based design of antiviral drug candidates targeting the SARS-CoV-2 main protease. Science 368: 1331-1335. 
  75. Jin Z, Du X, Xu Y, Deng Y, Liu M, Zhao Y, et al. 2020. Structure of M(pro) from SARS-CoV-2 and discovery of its inhibitors. Nature 582: 289-293. 
  76. Zhao Y, Fang C, Zhang Q, Zhang R, Zhao X, Duan Y, et al. 2022. Crystal structure of SARS-CoV-2 main protease in complex with protease inhibitor PF-07321332. Protein Cell 13: 689-693. 
  77. Zhang L, Lin D, Sun X, Curth U, Drosten C, Sauerhering L, et al. 2020. Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved α-ketoamide inhibitors. Science 368: 409-412. 
  78. Gunther S, Reinke PYA, Fernandez-Garcia Y, Lieske J, Lane TJ, Ginn HM, et al. 2021. X-ray screening identifies active site and allosteric inhibitors of SARS-CoV-2 main protease. Science 372: 642-646. 
  79. Cao B, Wang Y, Wen D, Liu W, Wang J, Fan G, et al. 2020. A trial of lopinavir-ritonavir in adults hospitalized with severe Covid-19. N. Engl. J. Med. 382: 1787-1799. 
  80. Gao X, Qin B, Chen P, Zhu K, Hou P, Wojdyla JA, et al. 2021. Crystal structure of SARS-CoV-2 papain-like protease. Acta Pharm. Sin. B. 11: 237-245. 
  81. Osipiuk J, Azizi SA, Dvorkin S, Endres M, Jedrzejczak R, Jones KA, et al. 2021. Structure of papain-like protease from SARS-CoV-2 and its complexes with non-covalent inhibitors. Nat. Commun. 12: 743. 
  82. Rut W, Lv Z, Zmudzinski M, Patchett S, Nayak D, Snipas SJ, et al. 2020. Activity profiling and crystal structures of inhibitor-bound SARS-CoV-2 papain-like protease: a framework for anti-COVID-19 drug design. Sci. Adv. 6: eabd4596. 
  83. Keating GM. 2016. Elbasvir/grazoprevir: first global approval. Drugs 76: 617-624. 
  84. Wang SJ, Huang CF, Yu ML. 2021. Elbasvir and grazoprevir for the treatment of hepatitis C. Exp. Rev. Anti-Infect. Ther. 19: 1071-1081. 
  85. Swierczynska M, Mirowska-Guzel DM, Pindelska E. 2022. Antiviral drugs in influenza. Int. J. Environ. Res. Public Health 19: 3018. 
  86. Dong G, Peng C, Luo J, Wang C, Han L, Wu B, et al. 2015. Adamantane-resistant influenza a viruses in the world (1902-2013): frequency and distribution of M2 gene mutations. PLoS One 10: e0119115. 
  87. Engel DA. 2013. The influenza virus NS1 protein as a therapeutic target. Antiviral Res. 99: 409-416. 
  88. Cho EJ, Xia S, Ma LC, Robertus J, Krug RM, Anslyn EV, et al. 2012. Identification of influenza virus inhibitors targeting NS1A utilizing fluorescence polarization-based high-throughput assay. J. Biomol. Screening 17: 448-459. 
  89. Gao Y, Yu X, Xue B, Zhou F, Wang X, Yang D, et al. 2014. Inhibition of hepatitis C virus infection by DNA aptamer against NS2 protein. PLoS One 9: e90333. 
  90. Alexopoulou A, Vasilieva L, Karayiannis P. 2020. New approaches to the treatment of chronic Hepatitis B. J. Clin. Med. 9: 3187. 
  91. Hussein M, Molina MA, Berkhout B, Herrera-Carrillo E. 2023. A CRISPR-cas cure for HIV/AIDS. Int. J. Mol. Sci. 24: 1563. 
  92. Kurt Yilmaz N, Schiffer CA. 2021. Introduction: drug resistance. Chem. Rev. 121: 3235-3237. 
  93. Du S, Hu X, Menendez-Arias L, Zhan P, Liu X. 2024. Target-based drug design strategies to overcome resistance to antiviral agents: opportunities and challenges. Drug Resist. Updat. 73: 101053. 
  94. Ouyang Y, Chen Y, Shang J, Sun S, Wang X, Huan S, et al. 2023. Virus-like plasmonic nanoprobes for quick analysis of antiviral efficacy and mutation-induced drug resistance. Anal. Chem. 95: 5009-5017. 
  95. Ahmadian E, Samiei M, Hasanzadeh A, Kavetskyy T, Jafari S, Alipour M, et al. 2020. Monitoring of drug resistance towards reducing the toxicity of pharmaceutical compounds: past, present and future. J. Pharm. Biomed. Anal. 186: 113265. 
  96. Van Poelvoorde LAE, Saelens X, Thomas I, Roosens NH. 2020. Next-generation sequencing: an eye-opener for the surveillance of antiviral resistance in influenza. Trends Biotechnol. 38: 360-367. 
  97. He Y, Guo Z, Subiaur S, Benegal A, Vahey MD. 2024. Antibody inhibition of influenza A virus assembly and release. J. Virol. 98: e0139823. 
  98. Matthys A, Saelens X. 2024. Promises and challenges of single-domain antibodies to control influenza. Antiviral Res. 222: 105807. 
  99. Liu Y, You Y, Lu Z, Yang J, Li P, Liu L, et al. 2019. N (6)-methyladenosine RNA modification-mediated cellular metabolism rewiring inhibits viral replication. Science 365: 1171-1176. 
  100. Li P, Liu Y, Song R, Zhao L, Yang J, Lu F, et al. 2022. RNA 2'-O-methyltransferase fibrillarin facilitates virus entry into macrophages through inhibiting type I interferon response. Front. Immunol. 13: 793582-793595. 
  101. Rani M, Sharma AK, Chouhan RS, Sur S, Mansuri R, Singh RK. 2024. Natural flavonoid pectolinarin computationally targeted as a promising drug candidate against SARS-CoV-2. Curr. Res. Struct. Biol. 7: 100120. 
  102. Fang PL, Cao YL, Yan H, Pan LL, Liu SC, Gong NB, et al. 2011. Lindenane disesquiterpenoids with anti-HIV-1 activity from Chloranthus japonicus. J. Nat. Prod. 74: 1408-1413. 
  103. Luo L, Jiang J, Wang C, Fitzgerald M, Hu W, Zhou Y, et al. 2020. Analysis on herbal medicines utilized for treatment of COVID-19. Acta Pharm. Sin. B. 10: 1192-1204. 
  104. Luo L, Yang J, Wang C, Wu J, Li Y, Zhang X, et al. 2022. Natural products for infectious microbes and diseases: an overview of sources, compounds, and chemical diversities. Sci. China Life Sci. 65: 1123-1145. 
  105. Ahmed-Belkacem R, Sutto-Ortiz P, Delpal A, Troussier J, Canard B, Vasseur JJ, et al. 2023. 5'-cap RNA/SAM mimetic conjugates as bisubstrate inhibitors of viral RNA cap 2'-O-methyltransferases. Bioorg. Chem. 143: 107035. 
  106. Ge R, Shen Z, Yin J, Chen W, Zhang Q, An Y, et al. 2022. Discovery of SARS-CoV-2 main protease covalent inhibitors from a DNA-encoded library selection. SLAS Discov. 27: 79-85. 
  107. Haider Z, Subhani MM, Farooq MA, Ishaq M, Khalid M, Akram MN, et al. 2020. In-silico pharmacophoric and molecular docking-based drug discovery against the Main Protease (Mpro) of SARS-CoV-2, a causative agent COVID-19. Pak. J. Pharm. Sci. 33: 2697-2705. 
  108. Liu J, Li K, Cheng L, Shao J, Yang S, Zhang W, et al. 2021. A high-throughput drug screening strategy against coronaviruses. Int. J. Infect. Dis. 103: 300-304. 
  109. Zhao Y, Du X, Duan Y, Pan X, Sun Y, You T, et al. 2021. High-throughput screening identifies established drugs as SARS-CoV-2 PLpro inhibitors. Protein Cell 12: 877-888.