RNA-dependent RNA polymerase (RdRp) domain of NS5 subunit of...

created [InstanceEdit:9923694] Stephan, Ralf, 2024-10-02
dbId 9923693
displayName RNA-dependent RNA polymerase (RdRp) domain of NS5 subunit of...
modified [InstanceEdit:9959926] Stephan, Ralf, 2025-07-03
schemaClass Summation
text RNA-dependent RNA polymerase (RdRp) domain of NS5 subunit of the DENV Replication Complex (RC) synthesizes a DENV nascent -ssRNA genome replicate from the +ssRNA template, using NTPs. The RdRp domain is involved in RNA replication in both the de novo initiation and the elongation steps (reviewed in van den Elsen et al., 2021). For instance, recombinant DENV-1 (strain S275/90) NS5 protein expressed in E. coli exhibits RNA-dependent RNA polymerase activity in vitro, consistent with its role in RNA synthesis (Tan et al., 1996). NS5 recognizes the stem?loop A (SLA) in the 5? untranslated region (UTR) of viral RNA; this recognition is a key aspect of replication (reviewed in Choi et al., 2021), and in vitro binding to 5'SLA has been demonstrated for DENV-2 (strain 3295) NS5 protein expressed in E. coli (Wang et al., 2022). The exact mechanism of replication is unclear (reviewed in van den Elsen et al., 2021).

Several FDA-approved small molecules inhibit NS5's RNA-dependent RNA-polymerase (RdRp) activity. Galidesivir (BCX4430) is an adenosine nucleoside analog that has successfully completed phase I clinical trials, involving SARS-CoV-2 and Marburg virus infections; it inhibits NS5 in vitro and reduces Dengue and Zika viral load (Deshpande et al., 2023; Julander et al., 2018). Entrectinib is an approved cancer therapeutic; it inhibits NS5 polymerase activity in in vitro biochemical assays (Yi et al., 2020). Sofosbuvir is approved for Hepatitis C virus (HCV) treatment; it acts as a chain terminator of DENV RNA replication (Xu et al., 2017; Sacramento et al., 2018; reviewed in Picarazzi et al., 2020).
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