Antiviral Sesquiterpene Lactones from Laurus nobilis L.: Inhibition of Hepatitis C Virus and Dengue Virus Replication

Natural products remain indispensable scaffolds in antiviral drug discovery, particularly against high-burden viral pathogens. In this study, two major sesquiterpene lactones, dehydrocostus lactone (1) and costunolide (2), were isolated from Laurus nobilis L. leaves and evaluated for their antiviral potential against hepatitis C virus (HCV) and dengue virus (DENV). The structures of both compounds were confirmed by HRMS and 1D NMR spectroscopic analyses. In subgenomic replicon assays, the molecules inhibited HCV replication in the low-micromolar range (EC50=2.34 μM for 1 and 2.06 μM for 2) with favorable selectivity indices. In full-length HCV reporter systems, costunolide (2) displayed enhanced anti-HCV potency, reduced viral RNA and NS5A protein levels, and enhanced the suppressive effect of the clinically approved NS5A inhibitor, daclatasvir. Furthermore, costunolide (2) exhibited cross-flaviviridae activity, suppressing DENV replication (EC50=5.89 μM in replicon cells; EC50=1.27 μM post-infection in infectious virus assays), and demonstrated cooperative suppression of viral propagation along with reduced glutathione. Mechanistically, these results highlight the critical role of the sesquiterpene lactone core, and the observed enhanced combined activity between costunolide and reduced glutathione is consistent with a possible contribution of the NRF2/glutathione antioxidant axis to its anti-DENV action. Overall, this study highlights L. nobilis as a previously underexplored source of antiviral sesquiterpene lactones and establishes costunolide (2) as a promising lead against HCV and DENV, warranting further investigation across additional Flaviviridae members.