Dengue virus serotype 2 RNA-dependent RNA polymerase (DENV-2 RdRp) (DENV-2 RdRp)

The Dengue virus serotype 2 RNA-dependent RNA polymerase (DENV-2 RdRp) is the catalytic domain located at the C-terminus of the non-structural protein 5 (NS5), the most conserved protein in the Dengue virus genome [UniProt P03314]. It is essential for the viral life cycle, as it mediates the replication of the positive-sense RNA genome and the transcription of viral mRNA [PubMed 24503063]. Because there is no direct human functional homolog for this enzyme, it is a primary target for the development of direct-acting antiviral drugs to treat Dengue fever and its severe manifestations, such as Dengue hemorrhagic fever [PubMed 28455118]. DENV-2 is a major global health concern, often associated with severe disease outbreaks and complex immune responses [NIH/CDC]. Therapeutic strategies targeting DENV-2 RdRp focus on two main classes: nucleoside inhibitors and non-nucleoside inhibitors. Nucleoside inhibitors, such as Balapiravir and NITD008, act as competitive substrates that incorporate into the growing RNA chain and cause premature termination [PubMed 19843797]. Non-nucleoside inhibitors bind to allosteric sites, such as the N-pocket, to prevent the conformational changes necessary for the enzyme to transition from initiation to elongation [PubMed 26109516]. Despite the potential of these inhibitors, significant challenges remain, including the need for high potency across all four serotypes and the avoidance of toxicity related to the inhibition of human mitochondrial polymerases [PubMed 22156314].

Other names

Non-structural protein 5NS5DENV2 NS5RNA-directed RNA polymeraseDengue virus 2 NS5 polymerase

Inhibition of viral RNA synthesis through competitive chain termination by nucleoside analogs or allosteric modulation of the polymerase domain by non-nucleoside inhibitors.