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.
Kan Li, Guangjin Fan, Wenyi Zhang et al.· ACS Infectious Diseases· 0 citations
Chikungunya virus (CHIKV), an arthropod-borne alphavirus, has emerged as a global health threat due to its rapid transmission and the lack of effective antiviral therapies. The cysteine protease activity of the virus-encoded nonstructural protein 2 (nsP2) is critical for CHIKV replication, as it processes viral polyproteins and counteracts host antiviral defenses, establishing it as a highly attractive target for therapeutic intervention. In this study, we present a rapid drug development platform that integrates covalent docking with direct-to-biology (D2B) synthesis and screening to identify nsP2 inhibitors. Candidates prioritized by in silico docking were synthesized and directly tested in FRET enzymatic assays without purification. This approach led to the identification of several nsP2 inhibitors with diverse chemical scaffolds, potent enzymatic inhibition, and antiviral activity. Together, these findings establish a streamlined strategy for covalent inhibitor development and provide promising leads for CHIKV antiviral development.
Zhengjun Cai, Kan Li, Sainetra Sridhar et al.· Journal of Medicinal Chemist...· 0 citations
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