Picornaviral RNA-dependent RNA polymerase and VPg protein (3D^pol^ and VPg)

Picornaviral RNA-dependent RNA polymerase (3D^pol^) is a viral enzyme essential for the replication of picornaviral genomes, catalyzing the synthesis of RNA from an RNA template[1][2][3][7][8]. Its activity requires the small viral protein VPg, which is covalently linked to the 5’ end of the genomic RNA and serves as a protein primer to initiate RNA replication after being uridylylated by the polymerase[1][2][5]. The 3D^pol^ enzyme is structurally and functionally homologous across Picornaviridae, containing the classical palm, thumb, and finger domains typical of viral RNA polymerases, and is the focal point of viral genome replication and polyadenylation[3][7][8]. The VPg protein is small (20-24 amino acids), and its interaction with 3D^pol^ is highly specific. The process of uridylylation of VPg by the polymerase allows viral RNA replication to begin, making both the polymerase and VPg essential to the viral life cycle and attractive targets for antiviral intervention[1][2][3][5]. However, current scientific and therapeutic standards typically treat these as related but distinct targets—VPg as a non-enzymatic protein cofactor/priming protein, and 3D^pol^ as an enzyme[3][5].

Other names

3D polymerase3D^pol^viral RNA polymeraseRdRpViral protein genome-linkedgenome-linked proteinVPg

Drugs targeting **3D^pol^** typically act as **nucleoside analogs** (incorporate into viral RNA and terminate replication or cause mutations) or **non-nucleoside inhibitors** (bind allosteric sites to block polymerase activity)[general knowledge]. Proposed VPg inhibitors would block **uridylylation** or interaction with the polymerase, preventing initiation of RNA synthesis[1][2].