The multiple roles of viral 3Dpol protein in picornavirus infections

Abstract

The Picornaviridae are a large group of positive-sense, single-stranded RNA viruses, and most research has focused on the Enterovirus genus, given they present a severe health risk to humans. Other picornaviruses, such as foot-and-mouth disease virus (FMDV) and senecavirus A (SVA), affect agricultural production with high animal mortality to cause huge economic losses. The 3D^pol protein of picornaviruses is widely known to be used for genome replication; however, a growing number of studies have demonstrated its non-polymerase roles, including modulation of host cell biological processes, viral replication complex assembly and localization, autophagy, and innate immune responses. Currently, there is no effective vaccine to control picornavirus diseases widely, and clinical therapeutic strategies have limited efficiency in combating infections. Many efforts have been made to develop different types of drugs to prohibit virus survival; the most important target for drug development is the virus polymerase, a necessary element for virus replication. For picornaviruses, there are also active efforts in targeted 3D^pol drug development. This paper reviews the interaction of 3D^pol proteins with the host and the progress of drug development targeting 3D^pol.

Keywords: 3Dpol; Picornaviruses; RNA-dependent RNA polymerase; RdRp inhibitor; virus-host interaction.

Figure 1.

A schematic representation of the EV-A71 genome and current understanding of the picornaviruses 3D^pro protein. The enterovirus 5” end is linked to a VPg followed by an IRES. After translation of the single OFR, the polyprotein is cascade cleaved to form VP1, VP2, VP3, VP4, 2A^pro, 2B, 2C, 3A, 3B, 3C^pro, and 3D^pol. at the 3” end of the EV-A71 genome is a polyA sequence. 3D^pol proteins catalyse viral RNA synthesis, catalyse VPg uridylation, interact with host proteins, and act as drug targets.

Figure 2.

Structures of the RdRps of picornaviruses. a: EV-A71 3D^pol protein (PDB: 3N6L); b: EV-D68 3D^pol protein (PDB: 6L4R); c: CVA16 3D^pol protein (PDB: 5Y6Z); d: CVB3 3D^pol protein (PDB: 3DDK); e: PV 3D^pol protein (PDB: 4K4S); and f: FMDV 3D^pol protein (PDB: 6S2L). The palm, thumb and finger subdomains are shown in blue, cyan and magenta, respectively.

Figure 3.

Diverse functions of the picornavirus 3D^pol protein and interactions with multiple host factors.

Figure 4.

Structures of nucleoside/nucleotide analog inhibitors.

Figure 5.

Structures of non-nucleoside inhibitors.

Figure 6.

X-ray crystal structure of 3D^pol and viral polymerase inhibitors. a: CVB3 3D^pol in complex with GPC-N114 (PDB: 4Y2A); b: EV-D68 3D^pol in complex with NADPH (PDB: 5ZIT). The palm, thumb and finger subdomains are shown in blue, cyan, and magenta cartoons, respectively. The inhibitors are shown in red sticks.