Targeting Picornavirus Nonstructural 2C Protein: Structure, Function, and Antiviral Discovery

Picornaviruses cause substantial human and veterinary disease, yet direct-acting antivirals remain limited. The nonstructural protein 2C is among the most conserved picornaviral proteins and has ATPase and helicase-like activities. 2C is involved in membrane remodeling, RNA replication, encapsidation, morphogenesis, and multiple virus-host interactions. In this review, we summarize the domain architecture and structural biology of 2C, highlighting the N-terminal membrane-binding region, the ATPase core, the C-terminal helical domain, and accessory motifs that regulate oligomerization and ligand recognition. We further review experimentally supported roles of 2C throughout the viral replication cycle and compare known inhibitors, resistance mutations, and emerging design strategies. Collectively, current evidence supports 2C as a tractable yet still underexploited antiviral target for medically important picornaviruses.