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

Abstract

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.

Keywords

Drug resistance / Drug design / Structural virology / Molecular dynamics / Protein oligomerization / AI-Driven drug discovery

CRediT authorship contribution statement

Mei Wang: Writing - original draft, Conceptualization. Haiyong Jia: Writing - review & editing, Visualization. Xinyong Liu: Writing review & editing, Visualization. Peng Zhan: Writing - review & editing, Visualization.

Ethics approval

Not applicable.

Declaration of generative AI in scientific writing

Not applicable.

Funding information

The authors are supported by the Key Research and Development Program, Ministry of Science and Technology of the People's Republic of China (No. 2023YFC2606500,2023YFE0206500).

Declaration of competing interests

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgments

Not applicable.

Data availability

Not applicable.

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