Insights into the antiviral mechanisms of β-caryophyllene: inhibiting viral spread and its synergy with acyclovir.

BACKGROUND: HSV-1 infections are pervasive in the general population of the world, and the gradual development of resistance to conventional antiviral therapies underlines the need to investigate alternative therapies. The present paper investigates the antiviral potential of a bicyclic sesquiterpene, β-caryophyllene (BCP), present in essential oils against Human alpha herpesvirus 1 (HSV-1). METHODS: The antiviral action of β-caryophyllene (BCP) was investigated using plaque reduction assays, molecular docking, molecular dynamics simulations, and surface plasmon resonance (SPR) analysis to explore its interactions with key surface glycoproteins of HSV-1 that are essential for viral entry and fusion: Glycoprotein B (gB), Glycoprotein C (gC), and Glycoprotein D (gD). RESULTS: BCP exhibited excellent antiviral activity, particularly during the pre-treatment phase, with a high selectivity index (SI) value of 35.86. Molecular docking analysis demonstrated that BCP binds strongly to glycoprotein B (gB) of HSV-1, with a binding energy of - 7.07 kcal/mol. These computational predictions were further validated by surface plasmon resonance (SPR) experiments, which confirmed a strong and specific interaction between BCP and gB, with a calculated equilibrium dissociation constant (KD) of (4.26 ± 0.02) × 10⁻⁶ M, supporting its proposed mechanism of action. DISCUSSION: Therefore, it was inferred that BCP interferes with viral entry and replication. Further confirmation through molecular dynamics simulation revealed less fluctuation in the Domain II region of gB, which might impede its fusion function. The SPR assay indeed confirmed that the BCP binds strongly to gB with a fast association and a slow dissociation rate, suggesting stability in this interaction. CONCLUSION: These findings suggest that BCP is a promising complementary therapy for HSV-1 infection, with the potential to reduce the emergence of drug resistance. However, further preclinical and clinical studies are warranted to fully validate its therapeutic efficacy and safety before patient application.