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Research Article Open access CC BY 4.0

How Much Potential Do Nucleoside Analogs Offer to Combat Human Corona Viruses?

Włodzimierz Buchowicz, Mariola Koszytkowska-Stawińska

Organics · pp. 71–110 · Published 8 May 2024

10.3390/org5020006

Abstract

Nucleoside analogs (NAs) have been extensively examined as plausible antiviral agents in recent years, in particular since the outbreak of the global pandemic of COVID-19 in 2019. In this review, the structures and antiviral properties of over 450 NAs are collected according to the type of virus, namely SARS-CoV, SARS-CoV-2, MERS-CoV, HCoV-OC43, HCoV-229E, and HCoV-NL63. The activity of the NAs against HCoV-related enzymes is also presented. Selected studies dealing with the mode of action of the NAs are discussed in detail. The repurposing of known NAs appears to be the most extensively investigated scientific approach towards efficacious anti-HCoV agents. The recently reported de novo-designed NAs seem to open up additional approaches to new drug candidates.

Corona (planetary geology) Nucleoside Virology Nucleoside analogue Biology Chemistry Stereochemistry Astrobiology

References (129)

  1. 1 Weiss, 2020, Forty Years with Coronaviruses [DOI]
  2. 2 Guarner, 2020, Three Emerging Coronaviruses in Two Decades [DOI]
  3. 3 WHO Regional Office for the Western Pacific (2006). SARS: How a Global Epidemic Was Stopped, WHO Regional Office for the Western Pacific.
  4. 4 Azhar, 2019, The Middle East Respiratory Syndrome (MERS) [DOI]
  5. 5 (2023, June 05). Middle East Respiratory Syndrome Coronavirus (MERS-CoV). Available online: https://www.who.int/health-topics/middle-east-respiratory-syndrome-coronavirus-mers.
  6. 6 (2023, June 05). Weekly Epidemiological Update on COVID-19—1 June 2023. Available online: https://www.who.int/publications/m/item/weekly-epidemiological-update-on-covid-19---1-june-2023.
  7. 7 (2023, June 05). WHO Chief Declares End to COVID-19 as a Global Health Emergency|UN News. Available online: https://news.un.org/en/story/2023/05/1136367.
  8. 8 Marra, 2003, The Genome Sequence of the SARS-Associated Coronavirus [DOI]
  9. 9 Kandeil, 2016, Complete Genome Sequence of Middle East Respiratory Syndrome Coronavirus Isolated from a Dromedary Camel in Egypt [DOI]
  10. 10 Naqvi, A.A.T., Fatima, K., Mohammad, T., Fatima, U., Singh, I.K., Singh, A., Atif, S.M., Hariprasad, G., Hasan, G.M., and Hassan, M.d.I. (2020). Insights into SARS-CoV-2 Genome, Structure, Evolution, Pathogenesis and Therapies: Structural Genomics Approach. Biochim. Biophys. Acta BBA Mol. Basis Dis., 1866. [DOI]
  11. 11 Morse, 2020, Learning from the Past: Possible Urgent Prevention and Treatment Options for Severe Acute Respiratory Infections Caused by 2019-nCoV [DOI]
  12. 12 Li, 2020, Therapeutic Options for the 2019 Novel Coronavirus (2019-nCoV) [DOI]
  13. 13 Martinez, 2020, Compounds with Therapeutic Potential against Novel Respiratory 2019 Coronavirus [DOI]
  14. 14 Gillner, 2019, Selected Nucleos(t)Ide-Based Prescribed Drugs and Their Multi-Target Activity [DOI]
  15. 15 Koren, 2003, Ribavirin in the Treatment of SARS: A New Trick for an Old Drug?
  16. 16 Barnard, 2006, Enhancement of the Infectivity of SARS-CoV in BALB/c Mice by IMP Dehydrogenase Inhibitors, Including Ribavirin [DOI]
  17. 17 Li, 2023, Therapeutic Strategies for COVID-19: Progress and Lessons Learned [DOI]
  18. 18 Horga, 2023, Phase II Study of Bemnifosbuvir in High-Risk Participants in a Hospital Setting with Moderate COVID-19 [DOI]
  19. 19 Jordan, 2018, Nucleosides for the Treatment of Respiratory RNA Virus Infections [DOI]
  20. 20 Pruijssers, 2019, Nucleoside Analogues for the Treatment of Coronavirus Infections [DOI]
  21. 21 Totura, 2019, Broad-Spectrum Coronavirus Antiviral Drug Discovery [DOI]
  22. 22 Yan, 2020, Research Progress of Drug Treatment in Novel Coronavirus Pneumonia [DOI]
  23. 23 Ami, 2021, Intriguing Antiviral Modified Nucleosides: A Retrospective View into the Future Treatment of COVID-19 [DOI]
  24. 24 Roy, 2022, Nucleosides and Emerging Viruses: A New Story [DOI]
  25. 25 Borbone, N., Piccialli, G., Roviello, G.N., and Oliviero, G. (2021). Nucleoside Analogs and Nucleoside Precursors as Drugs in the Fight against SARS-CoV-2 and Other Coronaviruses. Molecules, 26. [DOI]
  26. 26 Thames, 2022, Comparison of the Old and New—Novel Mechanisms of Action for Anti-Coronavirus Nucleoside Analogues [DOI]
  27. 27 Xu, X., Chen, Y., Lu, X., Zhang, W., Fang, W., Yuan, L., and Wang, X. (2022). An Update on Inhibitors Targeting RNA-Dependent RNA Polymerase for COVID-19 Treatment: Promises and Challenges. Biochem. Pharmacol., 205. [DOI]
  28. 28 Bekheit, 2023, Potential RNA-Dependent RNA Polymerase (RdRp) Inhibitors as Prospective Drug Candidates for SARS-CoV-2 [DOI]
  29. 29 Zenchenko, 2021, Nucleoside Inhibitors of Coronaviruses [DOI]
  30. 30 Cinatl, 2003, Glycyrrhizin, an Active Component of Liquorice Roots, and Replication of SARS-Associated Coronavirus [DOI]
  31. 31 Barnard, 2004, Inhibition of Severe Acute Respiratory Syndrome-Associated Coronavirus (SARSCoV) by Calpain Inhibitors and Beta-D-N4-Hydroxycytidine [DOI]
  32. 32 Barnard, 2006, Evaluation of Immunomodulators, Interferons and Known in Vitro SARS-CoV Inhibitors for Inhibition of SARS-Cov Replication in BALB/c Mice [DOI]
  33. 33 Asper, 2004, Application of Real-Time PCR for Testing Antiviral Compounds against Lassa Virus, SARS Coronavirus and Ebola Virus in Vitro [DOI]
  34. 34 Chen, 2004, In Vitro Susceptibility of 10 Clinical Isolates of SARS Coronavirus to Selected Antiviral Compounds [DOI]
  35. 35 Saijo, 2005, Inhibitory Effect of Mizoribine and Ribavirin on the Replication of Severe Acute Respiratory Syndrome (SARS)-Associated Coronavirus [DOI]
  36. 36 Sheahan, 2020, An Orally Bioavailable Broad-Spectrum Antiviral Inhibits SARS-CoV-2 in Human Airway Epithelial Cell Cultures and Multiple Coronaviruses in Mice [DOI]
  37. 37 Ikejiri, 2007, Synthesis and Biological Evaluation of Nucleoside Analogues Having 6-Chloropurine as Anti-SARS-CoV Agents [DOI]
  38. 38 Chu, 2006, Antiviral Activity of Nucleoside Analogues against SARS-Coronavirus (SARS-CoV) [DOI]
  39. 39 Dyall, 2014, Repurposing of Clinically Developed Drugs for Treatment of Middle East Respiratory Syndrome Coronavirus Infection [DOI]
  40. 40 Warren, 2014, Protection against Filovirus Diseases by a Novel Broad-Spectrum Nucleoside Analogue BCX4430 [DOI]
  41. 41 Peters, 2015, Design, Synthesis and Evaluation of a Series of Acyclic Fleximer Nucleoside Analogues with Anti-Coronavirus Activity [DOI]
  42. 42 Sheahan, 2017, Broad-Spectrum Antiviral GS-5734 Inhibits Both Epidemic and Zoonotic Coronaviruses [DOI]
  43. 43 Agostini, 2018, Coronavirus Susceptibility to the Antiviral Remdesivir (GS-5734) Is Mediated by the Viral Polymerase and the Proofreading Exoribonuclease [DOI]
  44. 44 Good, 2021, AT-527, a Double Prodrug of a Guanosine Nucleotide Analog, Is a Potent Inhibitor of SARS-CoV-2 In Vitro and a Promising Oral Antiviral for Treatment of COVID-19 [DOI]
  45. 45 Cho, 2006, Synthesis of Cyclopentenyl Carbocyclic Nucleosides as Potential Antiviral Agents Against Orthopoxviruses and SARS [DOI]
  46. 46 Cho, 2012, Synthesis and Antiviral Activity of a Series of 1′-Substituted 4-Aza-7,9-Dideazaadenosine C-Nucleosides [DOI]
  47. 47 Yoon, 2019, Design, Synthesis, and Anti-RNA Virus Activity of 6′-Fluorinated-Aristeromycin Analogues [DOI]
  48. 48 (2024, April 22). ClinicalTrials.gov [Internet]. U.S. National Library of Medicine. Identifier NCT03891420. A Study to Evaluate the Safety, Pharmacokinetics and Antiviral Effects of Galidesivir in Yellow Fever or COVID-19, Available online: https://classic.clinicaltrials.gov/ct2/show/NCT03891420?term=NCT03891420&draw=2&rank=1.
  49. 49 BioCryst (2023, June 19). Provides Update on Galidesivir Program|BioCryst Pharmaceuticals. Available online: https://ir.biocryst.com/news-releases/news-release-details/biocryst-provides-update-galidesivir-program.
  50. 50 Taylor, R., Bowen, R., Demarest, J.F., DeSpirito, M., Hartwig, A., Bielefeldt-Ohmann, H., Walling, D.M., Mathis, A., and Babu, Y.S. (2021). Activity of Galidesivir in a Hamster Model of SARS-CoV-2. Viruses, 14. [DOI]
  51. 51 Ogando, N.S., Zevenhoven-Dobbe, J.C., Jarhad, D.B., Tripathi, S.K., Lee, H.W., Jeong, L.S., Snijder, E.J., and Posthuma, C.C. (2021). 6′,6′-Difluoro-Aristeromycin Is a Potent Inhibitor of MERS-Coronavirus Replication. bioRxiv. [DOI]
  52. 52 Zandi, 2020, Repurposing Nucleoside Analogs for Human Coronaviruses [DOI]
  53. 53 Xie, 2021, Design and Development of an Oral Remdesivir Derivative VV116 against SARS-CoV-2 [DOI]
  54. 54 Schultz, 2022, Pyrimidine Inhibitors Synergize with Nucleoside Analogues to Block SARS-CoV-2 [DOI]
  55. 55 Wang, 2020, Remdesivir and Chloroquine Effectively Inhibit the Recently Emerged Novel Coronavirus (2019-nCoV) in Vitro [DOI]
  56. 56 Uemura, 2021, 5-Hydroxymethyltubercidin Exhibits Potent Antiviral Activity against Flaviviruses and Coronaviruses, Including SARS-CoV-2 [DOI]
  57. 57 Sacramento, 2021, In Vitro Antiviral Activity of the Anti-HCV Drugs Daclatasvir and Sofosbuvir against SARS-CoV-2, the Aetiological Agent of COVID-19 [DOI]
  58. 58 Ellinger, 2021, A SARS-CoV-2 Cytopathicity Dataset Generated by High-Content Screening of a Large Drug Repurposing Collection [DOI]
  59. 59 Bergant, 2022, Attenuation of SARS-CoV-2 Replication and Associated Inflammation by Concomitant Targeting of Viral and Host Cap 2′-O-Ribose Methyltransferases [DOI]
  60. 60 Bennett, 2022, Sangivamycin Is Highly Effective against SARS-CoV-2 in Vitro and Has Favorable Drug Properties [DOI]
  61. 61 Rabie, 2022, Potent Inhibitory Activities of the Adenosine Analogue Cordycepin on SARS-CoV-2 Replication [DOI]
  62. 62 Rabie, 2022, Efficacious Preclinical Repurposing of the Nucleoside Analogue Didanosine against COVID-19 Polymerase and Exonuclease [DOI]
  63. 63 Rabie, 2022, A Series of Adenosine Analogs as the First Efficacious Anti-SARS-CoV-2 Drugs against the B.1.1.529.4 Lineage: A Preclinical Repurposing Research Study [DOI]
  64. 64 Abdalla, M., and Rabie, A.M. (2023). Dual Computational and Biological Assessment of Some Promising Nucleoside Analogs against the COVID-19-Omicron Variant. Comput. Biol. Chem., 104. [DOI]
  65. 65 Rabie, 2022, Forodesine and Riboprine Exhibit Strong Anti-SARS-CoV-2 Repurposing Potential: In Silico and In Vitro Studies [DOI]
  66. 66 Rabie, 2023, Evaluation of a Series of Nucleoside Analogs as Effective Anticoronaviral-2 Drugs against the Omicron-B.1.1.529/BA.2 Subvariant: A Repurposing Research Study [DOI]
  67. 67 Lin, 2022, Azacytidine Targeting SARS-CoV-2 Viral RNA as a Potential Treatment for COVID-19 [DOI]
  68. 68 Yu, 2020, Azvudine (FNC): A Promising Clinical Candidate for COVID-19 Treatment [DOI]
  69. 69 Zhang, 2021, Azvudine Is a Thymus-Homing Anti-SARS-CoV-2 Drug Effective in Treating COVID-19 Patients [DOI]
  70. 70 Yu, 2022, The First Chinese Oral Anti-COVID-19 Drug Azvudine Launched
  71. 71 Milisavljevic, 2021, Antiviral Activity of 7-Substituted 7-Deazapurine Ribonucleosides, Monophosphate Prodrugs, and Triphoshates against Emerging RNA Viruses [DOI]
  72. 72 Schooley, 2021, Rethinking Remdesivir: Synthesis, Antiviral Activity, and Pharmacokinetics of Oral Lipid Prodrugs [DOI]
  73. 73 Lo, 2021, Broad-Spectrum In Vitro Antiviral Activity of ODBG-P-RVn: An Orally-Available, Lipid-Modified Monophosphate Prodrug of Remdesivir Parent Nucleoside (GS-441524) [DOI]
  74. 74 Cao, 2022, The Adenosine Analog Prodrug ATV006 Is Orally Bioavailable and Has Preclinical Efficacy against Parental SARS-CoV-2 and Variants [DOI]
  75. 75 Wen, Z.-H., Wang, M.-M., Li, L.-Y., Herdewijn, P., Snoeck, R., Andrei, G., Liu, Z.-P., and Liu, C. (2023). Synthesis and Anti-SARS-CoV-2 Evaluation of Lipid Prodrugs of β-D-N4-Hydroxycytidine (NHC) and a 3′-Fluoro-Substituted Analogue of NHC. Bioorganic Chem., 135. [DOI]
  76. 76 Bege, M., Kiss, A., Bereczki, I., Hodek, J., Polyák, L., Szemán-Nagy, G., Naesens, L., Weber, J., and Borbás, A. (2022). Synthesis and Anticancer and Antiviral Activities of C-2′-Branched Arabinonucleosides. Int. J. Mol. Sci., 23. [DOI]
  77. 77 (2023, September 24). Tonix Seeks to Advance OyaGen’s COVID-19 Treatment Under New Global Licensing Deal. Available online: https://www.biospace.com/article/tonix-seeks-to-advance-oyagen-s-covid-19-treatment-under-new-global-licensing-deal/.
  78. 78 Bibi, 2022, Cordycepin as a Promising Inhibitor of SARS-CoV-2 RNA Dependent RNA Polymerase (RdRp) [DOI]
  79. 79 Ye, Y. (2022). Nature, Springer Nature Limited.
  80. 80 McCarthy, 2023, VV116 as a Potential Treatment for COVID-19 [DOI]
  81. 81 Chan, 2013, Broad-Spectrum Antivirals for the Emerging Middle East Respiratory Syndrome Coronavirus [DOI]
  82. 82 Warren, 2016, Therapeutic Efficacy of the Small Molecule GS-5734 against Ebola Virus in Rhesus Monkeys [DOI]
  83. 83 Agostini, 2019, Small-Molecule Antiviral β-d-N4-Hydroxycytidine Inhibits a Proofreading-Intact Coronavirus with a High Genetic Barrier to Resistance [DOI]
  84. 84 Parang, K., El-Sayed, N.S., Kazeminy, A.J., and Tiwari, R.K. (2020). Comparative Antiviral Activity of Remdesivir and Anti-HIV Nucleoside Analogs against Human Coronavirus 229E (HCoV-229E). Molecules, 25. [DOI]
  85. 85 Andrei, 2017, Design, Synthesis, and the Biological Evaluation of a New Series of Acyclic 1,2,3-Triazole Nucleosides [DOI]
  86. 86 Pyrc, 2006, van der Inhibition of Human Coronavirus NL63 Infection at Early Stages of the Replication Cycle [DOI]
  87. 87 Bouvet, M., Debarnot, C., Imbert, I., Selisko, B., Snijder, E.J., Canard, B., and Decroly, E. (2010). In Vitro Reconstitution of SARS-Coronavirus mRNA Cap Methylation. PLoS Pathog., 6, Correction in PLoS Pathog. 2010, 6. [DOI]
  88. 88 Aouadi, 2016, Binding of the Methyl Donor S-Adenosyl-l-Methionine to Middle East Respiratory Syndrome Coronavirus 2′-O-Methyltransferase Nsp16 Promotes Recruitment of the Allosteric Activator Nsp10 [DOI]
  89. 89 Gordon, 2020, Remdesivir Is a Direct-Acting Antiviral That Inhibits RNA-Dependent RNA Polymerase from Severe Acute Respiratory Syndrome Coronavirus 2 with High Potency [DOI]
  90. 90 Ju, 2020, Nucleotide Analogues as Inhibitors of SARS-CoV Polymerase [DOI]
  91. 91 Chien, 2020, Nucleotide Analogues as Inhibitors of SARS-CoV-2 Polymerase, a Key Drug Target for COVID-19 [DOI]
  92. 92 Jockusch, 2020, Sofosbuvir Terminated RNA Is More Resistant to SARS-CoV-2 Proofreader than RNA Terminated by Remdesivir [DOI]
  93. 93 Lu, 2020, Development of a Simple In Vitro Assay To Identify and Evaluate Nucleotide Analogs against SARS-CoV-2 RNA-Dependent RNA Polymerase [DOI]
  94. 94 Devkota, 2021, Probing the SAM Binding Site of SARS-CoV-2 Nsp14 In Vitro Using SAM Competitive Inhibitors Guides Developing Selective Bisubstrate Inhibitors [DOI]
  95. 95 Klima, 2022, Crystal Structure of SARS-CoV-2 Nsp10–Nsp16 in Complex with Small Molecule Inhibitors, SS148 and WZ16 [DOI]
  96. 96 Li, F., Ghiabi, P., Hajian, T., Klima, M., Li, A.S.M., Khalili Yazdi, A., Chau, I., Loppnau, P., Kutera, M., and Seitova, A. (2023). SS148 and WZ16 Inhibit the Activities of Nsp10-Nsp16 Complexes from All Seven Human Pathogenic Coronaviruses. Biochim. Biophys. Acta Gen. Subj., 1867. [DOI]
  97. 97 Kuzikov, 2021, Identification of Inhibitors of SARS-CoV-2 3CL-Pro Enzymatic Activity Using a Small Molecule in Vitro Repurposing Screen [DOI]
  98. 98 Sourimant, 2022, 4′-Fluorouridine Is an Oral Antiviral That Blocks Respiratory Syncytial Virus and SARS-CoV-2 Replication [DOI]
  99. 99 Zhao, 2022, 5-Iodotubercidin Inhibits SARS-CoV-2 RNA Synthesis [DOI]
  100. 100 Schindewolf, 2023, SARS-CoV-2 Uses Nonstructural Protein 16 To Evade Restriction by IFIT1 and IFIT3 [DOI]
  101. 101 Guiraud, 2020, Synthesis of Adenine Dinucleosides SAM Analogs as Specific Inhibitors of SARS-CoV Nsp14 RNA Cap Guanine-N7-Methyltransferase [DOI]
  102. 102 Otava, 2021, The Structure-Based Design of SARS-CoV-2 Nsp14 Methyltransferase Ligands Yields Nanomolar Inhibitors [DOI]
  103. 103 Bobrovs, 2021, Potent SARS-CoV-2 mRNA Cap Methyltransferase Inhibitors by Bioisosteric Replacement of Methionine in SAM Cosubstrate [DOI]
  104. 104 Bobileva, O., Bobrovs, R., Sirma, E.E., Kanepe, I., Bula, A.L., Patetko, L., Ramata-Stunda, A., Grinberga, S., Jirgensons, A., and Jaudzems, K. (2023). 3-(Adenosylthio)Benzoic Acid Derivatives as SARS-CoV-2 Nsp14 Methyltransferase Inhibitors. Molecules, 28. [DOI]
  105. 105 Hausdorff, 2022, Potent Inhibition of SARS-CoV-2 Nsp14 N7-Methyltransferase by Sulfonamide-Based Bisubstrate Analogues [DOI]
  106. 106 Amador, 2022, Facile Access to 4′-(N-Acylsulfonamide) Modified Nucleosides and Evaluation of Their Inhibitory Activity against SARS-CoV-2 RNA Cap N7-Guanine-Methyltransferase Nsp14 [DOI]
  107. 107 Jung, 2022, Bisubstrate Inhibitors of Severe Acute Respiratory Syndrome Coronavirus-2 Nsp14 Methyltransferase [DOI]
  108. 108 Hausdorff, 2023, Structure-Guided Optimization of Adenosine Mimetics as Selective and Potent Inhibitors of Coronavirus Nsp14 N7-Methyltransferases [DOI]
  109. 109 Elis, 1972, New Indications for 6-Azauridine Treatment in Man. A Review [DOI]
  110. 110 Sun, 2015, Preclinical Pharmacokinetic Studies of 3-Deazaneplanocin A, a Potent Epigenetic Anticancer Agent, and Its Human Pharmacokinetic Prediction Using GastroPlusTM [DOI]
  111. 111 Bisel, 1970, Clinical Studies with Tubercidin Administered by Direct Intravenous Injection
  112. 112 (2024, April 22). ClinicalTrials.gov [Internet]. U.S. National Library of Medicine. Identifier NCT04280705. Adaptive COVID-19 Treatment Trial (ACTT), Available online: https://classic.clinicaltrials.gov/ct2/show/NCT04280705?term=NCT04280705&draw=2&rank=1.
  113. 113 (2024, April 22). ClinicalTrials.gov [Internet]. U.S. National Library of Medicine. Identifier NCT04292730. Study to Evaluate the Safety and Antiviral Activity of Remdesivir (GS-5734™) in Participants with Moderate Coronavirus Disease (COVID-19) Compared to Standard of Care Treatment, Available online: https://classic.clinicaltrials.gov/ct2/show/NCT04292730?term=NCT04292730&draw=2&rank=1.
  114. 114 (2024, April 22). ClinicalTrials.gov [Internet]. U.S. National Library of Medicine. Identifier NCT04292899. Study to Evaluate the Safety and Antiviral Activity of Remdesivir (GS-5734™) in Participants with Severe Coronavirus Disease (COVID-19), Available online: https://classic.clinicaltrials.gov/ct2/show/NCT04292899?term=NCT04292899&draw=2&rank=1.
  115. 115 (2024, April 22). ClinicalTrials.gov [Internet]. U.S. National Library of Medicine. Identifier NCT04401579. Adaptive COVID-19 Treatment Trial 2 (ACTT-2), Available online: https://classic.clinicaltrials.gov/ct2/show/NCT04401579?term=NCT04401579&draw=2&rank=1.
  116. 116 (2024, April 22). ClinicalTrials.gov [Internet]. U.S. National Library of Medicine. Identifier NCT04409262. A Study to Evaluate the Efficacy and Safety of Remdesivir Plus Tocilizumab Compared with Remdesivir Plus Placebo in Hospitalized Participants with Severe COVID-19 Pneumonia (REMDACTA), Available online: https://classic.clinicaltrials.gov/ct2/show/NCT04409262?term=NCT04409262&draw=2&rank=1.
  117. 117 (2024, April 22). ClinicalTrials.gov [Internet]. U.S. National Library of Medicine. Identifier NCT04492475. Adaptive COVID-19 Treatment Trial 3 (ACTT-3), Available online: https://classic.clinicaltrials.gov/ct2/show/NCT04492475?term=NCT04492475&draw=2&rank=1.
  118. 118 (2024, April 22). ClinicalTrials.gov [Internet]. U.S. National Library of Medicine. Identifier NCT04539262. Study in Participants with Early Stage Coronavirus Disease 2019 (COVID-19) to Evaluate the Safety, Efficacy, and Pharmacokinetics of Remdesivir Administered by Inhalation, Available online: https://classic.clinicaltrials.gov/ct2/show/NCT04539262?term=NCT04539262&draw=2&rank=1.
  119. 119 (2024, April 22). ClinicalTrials.gov [Internet]. U.S. National Library of Medicine. Identifier NCT04546581. Inpatient Treatment of COVID-19 with Anti-Coronavirus Immunoglobulin (ITAC), Available online: https://classic.clinicaltrials.gov/ct2/show/NCT04546581?term=NCT04546581&draw=2&rank=1.
  120. 120 (2024, April 22). ClinicalTrials.gov [Internet]. U.S. National Library of Medicine. Identifier NCT04583956. ACTIV-5/Big Effect Trial (BET-A) for the Treatment of COVID-19, Available online: https://classic.clinicaltrials.gov/ct2/show/NCT04583956?term=NCT04583956&draw=2&rank=1.
  121. 121 (2024, April 22). ClinicalTrials.gov [Internet]. U.S. National Library of Med-icine. Identifier NCT04593940. Immune Modulators for Treating COVID-19 (ACTIV-1 IM), Available online: https://classic.clinicaltrials.gov/ct2/show/NCT04593940?term=NCT04593940&draw=2&rank=1.
  122. 122 (2024, April 22). ClinicalTrials.gov [Internet]. U.S. National Library of Medicine. Identifier NCT04988035. ACTIV-5/Big Effect Trial (BET-C) for the Treatment of COVID-19, Available online: https://classic.clinicaltrials.gov/ct2/show/NCT04988035?term=NCT04988035&draw=2&rank=1.
  123. 123 (2024, April 22). ClinicalTrials.gov [Internet]. U.S. National Library of Medicine. Identifier NCT04405570. Safety, Tolerability and Efficacy of Molnupiravir (EIDD-2801) to Eliminate Infectious Virus Detection in Persons with COVID-19, Available online: https://classic.clinicaltrials.gov/ct2/show/NCT04405570?term=NCT04405570&draw=2&rank=1.
  124. 124 (2024, April 22). ClinicalTrials.gov [Internet]. U.S. National Library of Medicine. Identifier NCT04392219. COVID-19 First in Human Study to Evaluate Safety, Tolerability, and Pharmacokinetics of EIDD-2801 in Healthy Volunteers, Available online: https://classic.clinicaltrials.gov/ct2/show/NCT04392219?term=NCT04392219&draw=2&rank=1.
  125. 125 (2024, April 22). ClinicalTrials.gov [Internet]. U.S. National Library of Medicine. Identifier NCT04405739. The Safety of Molnupiravir (EIDD-2801) and Its Effect on Viral Shedding of SARS-CoV-2 (END-COVID), Available online: https://classic.clinicaltrials.gov/ct2/show/NCT04405739?term=NCT04405739&draw=2&rank=1.
  126. 126 (2024, April 22). ClinicalTrials.gov [Internet]. U.S. National Library of Medicine. Identifier NCT04575597. Efficacy and Safety of Molnupiravir (MK-4482) in Non-Hospitalized Adult Participants with COVID-19 (MK-4482-002), Available online: https://classic.clinicaltrials.gov/ct2/show/NCT04575597?term=NCT04575597&draw=2&rank=1.
  127. 127 (2024, April 22). ClinicalTrials.gov [Internet]. U.S. National Library of Medicine. Identifier NCT04709835. Study to Evaluate the Effects of AT-527 in Non-Hospitalized Adult Patients with Mild or Moderate COVID-19, Available online: https://classic.clinicaltrials.gov/ct2/show/NCT04709835?term=NCT04709835&draw=2&rank=1.
  128. 128 Kim, S.E. (2023, September 19). Long COVID: The Hunt for Causes and Cures. Available online: https://cen.acs.org/biological-chemistry/infectious-disease/Long-COVID-hunt-causes-cures/101/i30.
  129. 129 (2023, September 18). Virios Therapeutics Announces Positive Data Demonstrating Improvement in Multiple Long-COVID Symptoms Following Treatment with a Combination of Valacyclovir and Celecoxib in an Exploratory, Open-Label, Proof of Concept Study. Available online: https://ir.virios.com/news/press-releases/detail/100/virios-therapeutics-announcespositive-data-demonstrating.

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