Plant-derived tannins as anti-herpes simplex agents: A systematic review of in vitro evidence, molecular mechanisms, and therapeutic potential

Introduction: The herpes simplex virus (HSV), a double-stranded DNA virus, establishes persistent infections and frequently reactivates. While acyclovir and its derivatives remain first-line therapies, the emergence of drug-resistant HSV strains highlights an urgent need for alternative antiviral agents. Tannins, plant-derived polyphenolic compounds, have demonstrated potent in vitro antiviral activity against HSV. This review synthesizes current evidence on the anti-HSV properties of tannins, with emphasis on their mechanisms of actions. Methods: We systematically searched PubMed, ScienceDirect, Scopus, Chemical Abstracts, Google Scholar, and the Cochrane Library (۱۹۸۵–December ۲۰۲۴) using the keywords "Herpes simplex virus," "HSV," "antiviral," and "tannin." Results: Thirty-seven tannins from diverse botanical sources were identified in vitro for anti-HSV activity, with efficacy assessed via selectivity index (SI). Thirty-five compounds inhibited HSV-۱, among which pentagalloylglucose, tannic acid, and castalagin exhibited the strongest effects. Eight tannins showed anti-HSV-۲ activity, with chebulagic acid and chebulinic acid being most potent. Four compounds were tested against acyclovir-resistant strains, and pentagalloylglucose emerged as the most effective. Mechanistic studies revealed that tannins disrupt viral attachment, penetration, and membrane fusion, while also targeting key viral enzymes and structural proteins essential for replication and assembly. Conclusion: Tannins represent promising candidates for novel antivirals, particularly against acyclovir-resistant HSV. Further research is warranted to elucidate their mechanisms and translate these findings into clinical applications.