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<p>Herpes simplex virus type 1 (HSV-1) infects approximately 3.8 billion people worldwide, and the emergence of acyclovir-resistant strains has created an urgent need for antiviral agents with novel mechanisms of action. This review evaluates 124 polyphenolic compounds with documented anti-HSV-1 activity across 13 chemical classes, encompassing flavonoids (45.9%), hydrolyzable tannins (19.4%), and stilbenes (16.9%). Structure–activity relationship (SAR) analysis revealed that galloylation significantly enhances potency (median EC<sub>50</sub>: 1.50 µM vs. 6.39 µM for non-galloylated, <i>p</i> = 0.002), hydroxylation correlates inversely with EC<sub>50</sub> (Spearman <i>ρ </i>= −&#xa0;0.31, <i>p</i> = 0.012), and polymerization further augments activity (median EC<sub>50</sub>: 8.28 µM). Mechanistically, polyphenols act through multiple pathways, including virucidal activity (15.0%), adsorption inhibition (20.5%), DNA replication inhibition (9.4%), and immunomodulation via NF-κB (6.3%) and ROS-mediated pathways (9.4%), with 22 compounds (17.3%) exhibiting multi-target effects. Emerging sustainable production methods, including metabolic engineering, synthetic biology, and green extraction from agro-industrial waste, offer scalable approaches for polyphenol-based antiviral development. Polyphenols represent a promising class of anti-HSV-1 agents with multitarget mechanisms, a high genetic barrier to resistance, and proven activity against drug-resistant strains. Future directions include controlled clinical trials, formulation optimization for topical and systemic delivery and exploration of synergistic combinations with existing antivirals.</p>

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Antiviral effects of polyphenols against herpes simplex virus type 1: a comprehensive review

  • 期刊论文

  • 发表日期：

    2026年8月4日

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  • Alireza Mohebbi,
  • Fatemeh Sana Askari,
  • Mobina Madihi,
  • Seyed Hamidreza Monavari,
  • Farah Bokharaei-Salim,
  • Alijan Tabarraei,
  • Seyed Jalal Kiani

摘要

Herpes simplex virus type 1 (HSV-1) infects approximately 3.8 billion people worldwide, and the emergence of acyclovir-resistant strains has created an urgent need for antiviral agents with novel mechanisms of action. This review evaluates 124 polyphenolic compounds with documented anti-HSV-1 activity across 13 chemical classes, encompassing flavonoids (45.9%), hydrolyzable tannins (19.4%), and stilbenes (16.9%). Structure–activity relationship (SAR) analysis revealed that galloylation significantly enhances potency (median EC50: 1.50 µM vs. 6.39 µM for non-galloylated, p = 0.002), hydroxylation correlates inversely with EC50 (Spearman ρ = − 0.31, p = 0.012), and polymerization further augments activity (median EC50: 8.28 µM). Mechanistically, polyphenols act through multiple pathways, including virucidal activity (15.0%), adsorption inhibition (20.5%), DNA replication inhibition (9.4%), and immunomodulation via NF-κB (6.3%) and ROS-mediated pathways (9.4%), with 22 compounds (17.3%) exhibiting multi-target effects. Emerging sustainable production methods, including metabolic engineering, synthetic biology, and green extraction from agro-industrial waste, offer scalable approaches for polyphenol-based antiviral development. Polyphenols represent a promising class of anti-HSV-1 agents with multitarget mechanisms, a high genetic barrier to resistance, and proven activity against drug-resistant strains. Future directions include controlled clinical trials, formulation optimization for topical and systemic delivery and exploration of synergistic combinations with existing antivirals.