Abstract
The RNA-dependent RNA polymerase (RdRp) is an essential enzyme for the viral replication process, catalyzing the viral RNA synthesis using a metal ion-dependent mechanism. In recent years, RdRp has emerged as an optimal target for the development of antiviral drugs, as demonstrated by recent approvals of sofosbuvir and remdesivir against Hepatitis C virus (HCV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), respectively. In this work, we overview the main sequence and structural features of the RdRp of emerging RNA viruses such as Coronaviruses, Flaviviruses, and HCV, as well as inhibition strategies implemented so far. While analyzing the structural information available on the RdRp of emerging RNA viruses, we provide examples of success stories such as for HCV and SARS-CoV-2. In contrast, Flaviviruses’ story has raised attention about how the lack of structural details on catalytically-competent or ligand-bound RdRp strongly hampers the application of structure-based drug design, either in repurposing and conventional approaches.
Highlights
The replication of the viral genome is a complex mechanism in which several viral and host factors are involved
Mutagenic studies have shown that alterations in the process [7].structure of RNA can affect its interaction with the RNA-dependent RNA polymerase (RdRp) and interfere with the catalytic secondary
Hepatitis C virus (HCV) is a notable example of how coordinated and extensive research efforts can bring successful results in the development of potent and well-tolerated specific antiviral drugs. Both HCV and Severe Acute Respiratory Syndrome (SARS)-CoV-2 case studies might inspire the development of drugs against RNA viruses for which no effective cures are yet available despite high pathogenicity for humans
Summary
The replication of the viral genome is a complex mechanism in which several viral and host factors are involved. Once delivered into the host cell following virus entry and uncoating, the viral genome directs its own replication as well as translation of viral proteins. Most viruses coding for an RNA-dependent RNA polymerase (RdRp) complete these processes in the cytoplasm, with some notable exceptions (e.g., influenza virus). RdRp catalyzes the synthesis of a nascent RNA strand by adding ribonucleotide units to the 3’-hydroxyl terminus, building the RNA molecule in the 5’-3’ direction. To carry out its polymerase activity, RdRp requires an RNA template, ribonucleotide 5’ triphosphates (ATP, GTP, UTP, and CTP) as precursors of the nucleotide units of nascent RNA, and two magnesium ions (Mg2+ ) within the active site that catalyze the phosphodiester-bond formation.
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