Advances In SARS-COV-2 RdRp Inhibitors: A 2023-2024 Literature Review
Main Article Content
Abstract
Background: One of the major problems in drug design is to enhance the drug’s potency against genetic variants, for which adding a suitable pharmacophore to a newly designed molecule is preferred.
RNA-dependent RNA polymerase (RdRp) is the SARS-CoV-2 enzyme responsible for genome replication and gene transcription into the human cell.
Cryogenic Electron Microscopy resolved the first structure of the RdRp complex of SARS-CoV-2 in April 2020, followed by two other studies that reported similar structures that same year.
The RdRp complex is built up from several nonstructural proteins included nsp12, nsp7, and nsp8.
The protein nsp12 represents the core component and the catalytic subunit of RdRp, while nsp7 and nsp8 are accessory factors that increase the binding and processivity of the RdRp template.
The nsp12 subunit contains an N-terminal nidovirus RdRp-associated nucleotidyltransferase (NiRAN) domain, an interface domain and a C-terminal RdRp domain.
Subunits nsp7 and nsp8 bind to the thumb, and an additional copy of nsp8 binds to the fingers domain.
During replication, the active site of RdRp is responsible for incorporating free nucleotides into the daughter RNA strand of the replication complex.
RdRp inhibitors, once metabolized, compete with the viral ATP molecules for incorporation into the nascent RNA strand.
Once the RdRp drug replaces ATP in the new strand, the RNA synthesis process is terminated, thereby preventing further replication of the virus from occurring.
In several studies reviewed in this manuscript, Molecular Docking simulations was employed to screen inhibitors that showed binding interaction with the conserved residues of RdRp.
Aim: The purpose of the Review is to present a literature review from January 1, 2023, to April 30, 2024, on the advances in SARS-CoV-2 RdRp inhibitors as a therapeutic approach against the virus, emphasizing on the structure of the enzime, the non-structural proteins that comprises, in particular nsp12, nsp 8 and nsp 7, the mechanisms that underlie the antiviral activity of RdRp inhibitory substances, the structure of the nucleoside analogs that have demonstrated RdRp inhibition in structural biology and computational research studies, and examine the current understanding of the molecular mechanisms underlying the action of these nucleoside analogs.
Materials and Methods: Original scientific articles published in Medline, Pubmed, Science Direct, Web of Science, Scopus, EBSCO and BioMed Central databases, official health organizations (World Health Organization, U.S. Centers for Disease Control and Prevention, European Centre for Disease Prevention and Control) electronic publications, and specialized media in the subject, were electronically searched to accomplish the aim of the study. Articles published in any language were included from January 1, 2023, to April 30, 2024, using a variety of keywords in combination. The studies relevant to our review were analyzed and compared.
Results and Discussion:
Inhibition of RdRp´s has been an integral approach for managing various viral infections such as dengue, influenza, Hepatitis C (HCV), Bovine Viral Diarrhea Virus (BVDV), among others. Inhibition of the SARS-CoV-2 RdRp is currently rigorously explored for the treatment of COVID-19. Consequently, the importance of RdRp in developing anti-viral agents against this viral disease, has been discussed by the scientific community in the last four years. The structure activity relationship profile and binding conformations of the reported inhibitors are essential features to elucidate some hypothesis for the designing of further SARS-CoV-2 RdRp inhibitors.
The search on scientific literature on these inhibitors, the analyses of the interaction characteristics, together with the examination of the inhibitors chemical structure, it would guide the rational design of antiviral medications and research into viral transcriptional mechanisms.
Conclusions: Several RdRp inhibitors have shown promising results for their use in treating the SARS-CoV-2 virus.
While work must still be conducted to fully understand the mechanisms responsible for reducing the antiviral activity of SARS-CoV-2, their potential in healing infected individuals is extremely valuable.
The development of SARS-CoV-2 RdRp inhibitors, to relieve the severity of an infection for a SARS-CoV-2 variants that could emerge in the near future, it is an essential task for the scientific community.
The analyses of inhibitors chemical structure-RdRp, besides the analyses of the inhibitors-RdRp interactions, it would guide the rational design of antiviral medications and research into SARS-CoV-2 transcriptional mechanisms.
This review summarizes recent progress in studies of RdRp inhibitors, 87 compounds was tested, focusing on the chemical structure of the inhibitors and the interactions between these inhibitors and the enzyme complex.
Article Details
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
2. Gao Y, Yan L, Huang Y. et al. Structure of the RNA-dependent RNA polymerase from COVID-19 virus. Science. 2020;368:779–782. https://doi.org/10.1126/science.abb7498/
3. Ahn D, Choi J, Taylor D. et al. Biochemical characterization of a recombinant SARS coronavirus nsp12 RNA-dependent RNA polymerase capable of copying viral RNA templates. Arch. Virol. 2012;157:2095–2104. https://doi.org/10.1007/s00705-012-1404-x/
4. Kirchdoerfer R, Ward A. Structure of the SARS-CoV nsp12 polymerase bound to nsp7 and nsp8 co-factors. Nat. Commun. 2019;10:2342. https://doi.org/10.1038/s41467-019-10280-3/
5. Yadav A, Kumar Sh, Maurya Sh. et al. Interface design of SARS-CoV-2 symmetrical nsp7 dimer and machine learning-guided nsp7 sequence prediction reveals physicochemical properties and hotspots for nsp7 stability, adaptation, and therapeutic design. Phys. Chem. Chem. Phys. Advance Article. 2024;26:14046-14061. https://pubs.rsc.org/en/content/articlelanding/2024/cp/d4cp01014k/
6. Metwally K, Abo-Dya N, Issa M. et al. The Unusual Architecture of RNA-Dependent RNA Polymerase (RdRp)’s Catalytic Chamber Provides a Potential Strategy for Combination Therapy against COVID-19. Molecules. 2023;28:2806. https://doi.org/10.3390/molecules28062806/
7. Yin W, Luan X, Li Z. et al. Structural basis for inhibition of the SARS-CoV-2 RNA polymerase by suramin. Nat. Struct. Mol. Biol. 2021;28:319-325. https://doi.org/10.1038/s41594-021-00570-0/
8. Kloostra S. Sitemap. Joomla! 3 SEO and Performance; Apress: New York, NY, USA, 2015. https://www.amazon.com/Joomla-SEO-Performance-Simon-Kloostra/dp/1484211251/
9. Wu J, Chen Zh, Han X. et al. SARS-CoV-2 RNA-dependent RNA polymerase as a target for high-throughput drug screening. Future Virol. 2023;18(1):51-62. https://www.futuremedicine.com/doi/10.2217/fvl-2021-0335/
10. Cheng A, Zhang W, Xie Y. et al. Expression, purification, and characterization of SARS coronavirus RNA polymerase. Virology. 2005;335(2):165–176. https://pubmed.ncbi.nlm.nih.gov/15840516/
11. Velthuis A, Arnold J, Cameron C. et al. The RNA polymerase activity of SARS-coronavirus nsp12 is primer dependent. Nucleic Acids Res. 2010;38(1):203–214. https://pubmed.ncbi.nlm.nih.gov/19875418/
12. Yin W, Mao Ch, Luan X. et al. Structural basis for inhibition of the RNA-dependent RNA polymerase from SARS-CoV-2 by remdesivir. Science. 2020;368(6498):1499-1504. https://pubmed.ncbi.nlm.nih.gov/32358203/
13. Woods W, Umansky T, Ramesh N. et al. Discovery of RdRp Thumb-1 as a novel broad-spectrum antiviral family of targets and MDL-001 as a potent broad-spectrum inhibitor thereof - Part I: A Bioinformatics and Deep Learning Approach. bioRxiv. 2024;03.29:1-19. https://doi.org/10.1101/2024.03.29.587401/
14. Eltahla A, Luciani F, White P. et al. Inhibitors of the Hepatitis C Virus Polymerase; Mode of Action and Resistance. Viruses. 2015;7(10): 520624. https://pubmed.ncbi.nlm.nih.gov/26426038/
15. Lesburg C, Cable M, Ferrari, E. et al. Crystal structure of the RNA-dependent RNA polymerase from hepatitis C virus reveals a fully encircled active site. Nat Struct Mol Biol. 1999;6:937–943. https://pubmed.ncbi.nlm.nih.gov/26426038/
16. van der Maaten L, Hinton G. Visualizing Data using t-SNE. Journal of Machine Learning Research. 2008;9:2579-2605. https://jmlr.org/papers/volume9/vandermaaten08a/vandermaaten08a.pdf/
17. Nguyen L. Model medicines’ oral anti-covid-19 drug candidate MDL-001 found to significantly reduce viral load in lungs; accepted into NIH’s Antiviral Program for Pandemics. Model Medicines. 2023;12:20. https://www.modelmedicines.com/newsroom/mdl-001-viral-load-covid19/
18. Xu T, Zhang L. Current understanding of nucleoside analogs inhibiting the SARS-CoV-2 RNA-dependent RNA polymerase. Comput Struct Biotechnol J. 2023;21:4385-4394. https://doi.org/10.1016/j.csbj.2023.09.001/
19. Wu J, Chen Z, Han X. et al. SARS-CoV-2 RNA-dependent RNA polymerase as a target for high-throughput drug screening. Future Virol. 2023;18:1. https://doi.org/10.2217/fvl-2021-0335/
20. Gong P. Within and beyond the nucleotide addition cycle of viral RNA-dependent RNA polymerases. Front Mol Biosci. 2022;10:1. https://doi.org/10.3389/fmolb.2021.822218/
21. Malone B, Perry J, Olinares P. et al. Structural basis for substrate selection by the SARS-CoV-2 replicase. Nature. 2023;614:781-787. https://doi.org/10.1038/s41586-022-05664-3/
22. Johnson K, Dangerfield T. Mechanisms of inhibition of viral RNA replication by nucleotide analogs. Enzymes. 2021;49:39-62. https://doi.org/10.1016/bs.enz.2021.07.001/
23. Bravo J, Dangerfield T, Taylor D. et al. Remdesivir is a delayed translocation inhibitor of SARS-CoV-2 replication. Mol Cell. 2021;81:1548-1552. https://doi.org/10.1016/j.molcel.2021.01.035/
24. Gordon C, Lee H, Tchesnokov E. et al. Efficient incorporation and template-dependent polymerase inhibition are major determinants for the broad-spectrum antiviral activity of remdesivir. J Biol Chem. 2022;298:2. https://doi.org/10.1016/j.jbc.2021.101529/
25. Khan S, Attar F, Bloukh S. et al. A review on the interaction of nucleoside analogues with SARS-CoV-2 RNA dependent RNA polymerase. Int J Biol Macromol. 2021;181:605-611. https://doi.org/10.1016/j.ijbiomac.2021.03.112/
26. Biteau N, Amichai S, Azadi N. et al. Synthesis of 4'-substituted carbocyclic uracil derivatives and their monophosphate prodrugs as potential antiviral agents. Viruses. 2023;15:544. https://www.mdpi.com/1999-4915/15/2/544/
27. Schultz D, Johnson R, Ayyanathan K. et al. Pyrimidine inhibitors synergize with nucleoside analogues to block SARS-CoV-2. Nature. 2022;604:134-140. https://doi.org/10.1038/s41586-022-04482-x/
28. Zhao J, Guo S, Yi D. et al. A cell-based assay to discover inhibitors of SARS-CoV-2 RNA dependent RNA polymerase. Antivir Res. 2021;190:105078. https://doi.org/10.1016/j.antiviral.2021.105078/
29. Gana A, Baraniuk J. Identification of a New Drug Binding Site in the RNA-Dependent-RNA-Polymerase (RdRp) Domain. BioMedInformatics. 2023;3:885-907. https://doi.org/10.3390/biomedinformatics3040055/
30. Piplani S, Singh P, Winkler D. et al. Computationally repurposed drugs and natural products against RNA dependent RNA polymerase as potential COVID-19 therapies. Mol. Biomed. 2021;2:28. https://doi.org/10.1186/s43556-021-00050-3/
31. Malone B, Perry J, Olinares P. et al. Structural basis for substrate selection by the SARS-CoV-2 replicase. Nature. 2023;614:781-87. https://doi.org/10.1038/s41586-022-05664-3/
32. Peersen O. A Comprehensive Superposition of Viral Polymerase Structures. Viruses. 2019;11:745. https://doi.org/10.3390/v11080745/
33. Rehman H, Sajjad M, Akhtar M. et al. Identification of RdRp inhibitors against SARS-CoV-2 through E-pharmacophore-based virtual screening, molecular docking and MD simulations approaches. International Journal of Biological Macromolecules. 2023;237:124169. https://doi.org/10.1016/j.ijbiomac.2023.124169/
34. Shivanyuk A, Ryabukhin S, Bogolyubsky A. et al. Chimica Oggi-Chemistry Today. 2007;25:6. https://www.researchgate.net/publication/287001659/
35. Rather M, Dutta S, Guttula P. et al. Structural analysis, molecular docking and molecular dynamics simulations of G-protein-coupled receptor (kisspeptin) in fish, J. Biomol. Struct. Dyn. 2020;38:2422-2439. https://doi.org/10.1080/07391102.2019.1633407/
36. Ali J, Aldahham B, Rabeea M. et al. Synthesis, characterization and in-silico assessment of novel thiazolidinone derivatives for cyclin-dependent kinases-2 inhibitors. Journal of Molecular Structure. 2021;1223:129311. https://doi.org/10.1016/j.molstruc.2020.129311/
37. Genheden S, Ryde U. The MM/PBSA and MM/GBSA methods to estimate ligand-binding affinities. Expert Opin Drug Discov. 2015;10(5):449-61. https://doi.org/10.1517/17460441.2015.1032936/
38. Opo F, Rahman M, Ahammad F. et al. Structure based pharmacophore modeling, virtual screening, molecular docking and ADMET approaches for identification of natural anti-cancer agents targeting XIAP protein. Sci Rep. 2021;11:4049. https://doi.org/10.1038/s41598-021-83626-x/
39. Aziz S, Wagas M, Kumar T. et al. Identifying non-nucleoside inhibitors of RNA-dependent RNA-polymerase of SARS-CoV-2 through per-residue energy decomposition-based pharmacophore modeling, molecular docking, and molecular dynamics simulation. Journal of Infection and Public Health. 2023;16(4):501-519. https://doi.org/10.1016/j.jiph.2023.02.009/
40. Naqvi A, Mohammad T, Hasan G. et al. Advancements in docking and molecular dynamics simulations towards ligand-receptor Interactions and Structure-function Relationships. Curr Top Med Chem. 2019;18:1755-68. https://doi.org/10.2174/1568026618666181025114157/
41. Isaac T, Quadry O, Ooreoluwa T. et al. Molecular Mechanics with Generalized Born Surface Area (MMGBSA) Calculations and Docking Studies Unravel some Antimalarial Compounds Using Heme O Synthase as Therapeutic Target. Chemistry Europe. 2023;8:48. https://doi.org/10.1002/slct.202303686/
42. Alrehaily A, Elfiky A, Ibrahim I. et al. Novel sofosbuvir derivatives against SARS-CoV-2 RNA-dependent RNA polymerase: an in silico perspective. Sci Rep. 2023;13:23080. https://doi.org/10.1038/s41598-023-49712-y/
43. Roozbeh F, Saeedi M, Alizadeh-Navaei, R. et al. Sofosbuvir and daclatasvir for the treatment of COVID-19 outpatients: A double-blind, randomized controlled trial. J. Antimicrob. Chemother. 2021;76(3):753-757. https://doi.org/10.1093/jac/dkaa501/
44. https://plip-tool.biotec.Tu-dresden.de/plipweb/plip/index/
45. https://www.schrodinger.com/platform/products/pymol/
46. Bekheit M, Panda S, Girgis A. et al. Potential RNA-dependent RNA polymerase (RdRp) inhibitors as prospective drug candidates for SARS-CoV-2. European Journal of Medicinal Chemistry. 2023;252:115292. https://doi.org/10.1016/j.ejmech.2023.115292/
47. Newman D, Cragg G. Natural products as sources of new drugs from 1981 to 2014. J. Nat. Prod. 2016;79:629-661. https://doi:10.1021/acs.jnatprod.5b01055/
48. De Clercq E, Li G. Approved antiviral drugs over the past 50 years. Clin. Microbiol. Rev. 2016;29:695i747. https://doi.org/10.1128/cmr.00102-15/
49. Girgis A, D'Arcy P, Aboshouk D. et al. Synth/esis and bio-properties of 4-piperidone containing compounds as curcumin mimics. RSC Adv. 2022;12:31102-31123. http://doi:10.1039/d2ra05518j/
50. Nelson K, Dahlin J, Bisson J. The essential medicinal chemistry of curcumin. J. Med. Chem. 2017;60:1620-1637. http://doi:10.1021/acs.jmedchem.6b00975/
51. Chakravarti R, Singh R, Ghosh A. et al. A review on potential of natural products in the management of COVID-19. RSC Adv. 2021;11:16711-16735. http://doi:10.1039/d1ra00644d/
52. Thomas E, Stewart L, Darley B. A.M. et al. Plant-based natural products and extracts: potential source to develop new antiviral drug candidates. Molecules. 2021;26:6197. https://www.mdpi.com/1420-3049/26/20/6197/
53. Owen L, Laird K, Shivkumar M. Antiviral plant-derived natural products to combat RNA viruses: targets throughout the viral life cycle. Lett. Appl. Microbiol. 2021;75:476-499. http://doi:10.1111/lam.13637/
54. Khater S, Kumar P, Dasgupta N. et al. Combining SARS-CoV-2 proofreading exonuclease and RNA-dependent RNA polymerase inhibitors as a strategy to combat COVID-19: a high-throughput in silico screening. Front. Microbiol. 2021;12:647693. https://doi:10.3389/fmicb.2021.64769/
55. Shehzadi K, Saba A, Yu M. et al. Structure-Based Drug Design of RdRp Inhibitors against SARS-CoV-2. Top Curr Chem (Z). 2023;381:22. https://doi.org/10.1007/s41061-023-00432-x/
56. Gordon C, Tchesnokov P, Feng J. et al. The antiviral compound remdesivir potently inhibits RNA-dependent RNA polymerase from Middle East respiratory syndrome coronavirus. J Biol Chem. 2020;295(15):4773-4779. https://doi.org/10.1074/jbc.AC120.013056/
57. Ahmed M, Farag A, Boys I. et al. FDA approved drugs with antiviral activity against SARS-CoV-2: From structure-based repurposing to host-specific mechanisms. Biomed Pharmacother. 2023;162:114614. https://doi.org/10.1016/j.biopha.2023.114614/
58. https://mybiosoftware.com/biovia-discovery-studio-visualizer-4-5-molecular-visualization.html/
59. Elkaeed E, Alsfouk B, Metwaly A. et al. Computer-assisted drug discovery of potential natural inhibitors of the SARS-CoV-2 RNA-dependent RNA polymerase through a multi-phase in silico approach. Antiviral Therapy. 2023;28(5). https://journals.sagepub.com/doi/10.1177/13596535231199838/
60. Elkaeed E, Elkady H, Belal A. et al. Multi-Phase In Silico Discovery of Potential SARS-CoV-2 RNA-Dependent RNA Polymerase Inhibitors among 3009 Clinical and FDA-Approved Related Drugs. Processes. 2022;10(3):530. https://doi.org/10.3390/pr10030530/
61. Amin S, Banerjee S, Singh S. et al. First structure-activity relationship analysis of SARS-CoV-2 virus main protease (Mpro) inhibitors: an endeavor on COVID-19 drug discovery. Mol Divers. 2021;25(3):1827–1838. https://doi.org/10.1007/s11030-020-10166-3/
62. Sartori G, Nascimento A. Comparative Analysis of Electrostatic Models for Ligand Docking. Front Mol Biosci. 2019;6:52. https://doi.org/10.3389/fmolb.2019.00052/
63. Morales-Bayuelo A, Sánchez-Márquez J. New findings on ligand series used as SARS-CoV-2 virus inhibitors within the frameworks of molecular docking, molecular quantum similarity and chemical reactivity indices, Version 3. F1000Research. 2023;11:914. Last updated: 13 APR 2024. https://f1000research.com/articles/11-914/v3/
64. Morales-Bayuelo A: New insights in series of ligands used as SARS-CoV-2 virus inhibitors within molecular docking, molecular quantum similarity, and chemical reactivity indices frameworks. Harvard Dataverse, V1. [Dataset].2022. https://doi.org/10.12688/F1000RESEARCH.123550.1/
65. Morales-Bayuelo A, Matute R, Caballero J. New Insights from the CoMSIA Analysis within the Framework of Density Functional Theory. J Mol Model. 2015;21:156. https://bit.ly/3GLDQLs/
66. Friesner R, Banks J, Murphy R. et al. Glide: A New Approach for Rapid, Accurate Docking and Scor- ing. 1. Method and Assessment of Docking Accuracy. J. Med. Chem. 2004;47:1739-1749. https://doi.org/10.1021/jm0306430/
67. Tóth L, Krejčová, K, Dejmek M. et al. Novel analogues of a nonnucleoside SARS-CoV-2 RdRp inhibitor as potential antivirotics. Beilstein J. Org. Chem. 2024;20:1029-1036. https://doi.org/10.3762/bjoc.20.91/
68. Tarantino D, Cannalire R, Mastrangelo E. et al. Targeting flavivirus RNA dependent RNA polymerase through a pyridobenzothiazole inhibitor. Antiviral Res. 2016;134:226-235. https://doi.org/10.1016/j.antiviral.2016.09.007/
69. Cannalire R, Chan K, Burali K. et al. Pyridobenzothiazolones exert potent anti-dengue activity by hampering multiple functions of NS5 polymerase. ACS Med. Chem. Lett. 2020;11:773-782. https://doi.org/10.1021/acsmedchemlett.9b00619/
70. Wardakhan W, El-Sayed N. New Approaches for the Synthesis of 1,3,4-Thiadiazole and 1,2,4-Triazole Derivatives with Antimicrobial Activity. Phosphorus, Sulfur Silicon Relat. Elem. 2009;184:790-804. https://doi.org/10.1080/10426500802274534/
71. Targowska‐Duda K, Maj M, Drączkowski P. et al. WaterMap‐Guided Structure‐Based Virtual Screening for Acetylcholinesterase Inhibitors. ChemMedChem. 2022;17:e202100721. http://doi.org/10.1002/cmdc.202100721/
72. Dejmek M, Konkoľová E, Eyer L. et al. Non-Nucleotide RNA-Dependent RNA Polymerase Inhibitor That Blocks SARS-CoV-2 Replication. Viruses. 2021;13:1585. https://doi.org/10.3390/v13081585/
73. Gordon C, Walker S, Tchesnokov E. et al. Mechanism and spectrum of inhibition of a 4´-cyano modified nucleotide analog against diverse RNA polymerases of prototypic respiratory RNA viruses”. bioRxiv. 2024. https://doi.org/10.1101/2024.04.22.590607/
74. Siegel D, Hui, H, Pitts J. et al. Discovery and Synthesis of GS-7682, a Novel Prodrug of a 4’-CN-4-Aza-7,9-Dideazaadenosine C-Nucleoside with Broad-Spectrum Potency Against Pneumo- and Picornaviruses and Efficacy in RSV-Infected African Green Monkeys. bioRxiv, 2024. https://doi.org/10.1101/2024.04.17.589937/
75. Stevens L, Pruijssers, A, Lee, H. et al. Mutations in the SARS-CoV-2 RNA-dependent RNA polymerase confer resistance to remdesivir by distinct mechanisms. Science translational medicine. 2022;14(656):eabo0718. https://doi.org/10.1126/scitranslmed.abo0718/