Dual-site targeting of Zika virus NS5 RNA-dependent RNA polymerase reveals novel nucleoside and allosteric inhibitor scaffolds

Zika virus (ZIKV) remains a significant global health concern due to its association with severe neurological complications and the lack of approved antiviral therapies. The viral non-structural protein 5 (NS5), particularly its RNA-dependent RNA polymerase (RdRp) domain, is essential for viral replication and immune evasion and lacks a human homolog, making it an attractive antiviral target. Using an integrated structure-guided virtual screening approach, two distinct classes of small-molecule