Advances In SARS-COV-2 RdRp Inhibitors: A 2023-2024 Literature Review
Authors: Cobar Oscar , Cobar Stella 
Published: August 2024

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.