Viral drug resistance has emerged as a major challenge in clinical antiviral therapy. The efficacy of existing antiviral agents is frequently compromised by viral mutations, and there remains a significant gap in comprehensive cross-viral analyses of resistance mechanisms as well as in the development of systematic anti-resistance design strategies.
In this study, a research team from Shandong University and Shandong Second Medical University conducted a comparative analysis of resistance patterns across both RNA viruses—including SARS-CoV-2, HIV-1, and influenza A virus (IAV)—and DNA viruses—namely monkeypox virus (MPXV) and hepatitis B virus (HBV). The researchers identified three core molecular mechanisms underlying drug resistance: “steric hindrance interference”, “conformational remodeling”, and “oligomerization alteration”, which elucidate how specific mutations (e.g., SARS-CoV-2 E166V) impair drug binding.
Furthermore, the study proposed five innovative strategies to counteract resistance: “dynamic flexibility adaptation”, “multivalent interactions”, “oligomerization regulation”, “molecular glue stabilization”, and “hydrophobic tagging-driven degradation”. Promising results were demonstrated through representative candidate compounds: GC376 exhibited potent inhibition against the SARS-CoV-2 E166V mutant; 5i3 maintained nanomolar-level activity against the HIV-1 GH9-resistant strain; tecovirimat effectively targeted MPXV envelope assembly; compound 24 engaged conserved interfaces of IAV; and HyT-S7 showed efficacy in overcoming HBV-associated drug resistance. Notably, the team integrated advanced artificial intelligence tools—including DiffDock, REINVENT, and AlphaFold2—to establish a novel drug discovery paradigm, substantially enhancing the efficiency and precision of anti-resistance therapeutic development.
This study offers essential theoretical insights into overcoming clinical antiviral drug resistance. The article titled “Conquering Viral Drug Resistance: Structural and Mechanistic Paradigms for Anti-Resistance Drug Design” has been published in Pharmaceutical Science Advances on September 22, 2025.
DOI: 10.1016/j.pscia.2025.100094