Conquering viral drug resistance: Structural and mechanistic paradigms for antiresistance drug design

Viral drug resistance remains a critical challenge in antiviral therapy. This perspective highlights five studies on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), human immunodeficiency virus type 1 (HIV-1), monkeypox virus (MPXV), influenza A virus (IAV), and Hepatitis B virus (HBV), revealing novel resistance mechanisms and innovative strategies. For SARS-CoV-2, GC376's flexible benzyl group overcomes nirmatrelvir resistance. HIV-1's non-nucleoside reverse transcriptase inhibitors (NNRTIs) 5i3 adapts to resistant mutants via a quinazoline scaffold, while MPXV's tecovirimat acts as a “molecular glue” stabilizing F13 dimers. Expanding these paradigms, we present groundbreaking insights: An indazole-based IAV inhibitor (compound 24) disrupts the conserved PA-PB1 heterodimer, showing sub-micromolar potency against resistant strains. For HBV, a hydrophobic tagging degrader (HyT-S7) induces HBc degradation, bypassing resistance mutations impairing traditional capsid modulators. Key strategies include dynamic flexibility, multivalent interactions, and oligomerization control, integrated with AI-driven design and real-time surveillance. This perspective bridges structural insights with translational applications, offering a roadmap for next-generation, mutation-resilient antivirals.