Abstract
Elucidating the ecological functions of natural products in plant adaptive mechanisms is an emerging means of discovering lead compounds. Here, we show an undescribed plant glandular trichome-specific defense sesterterpenoid, leucosceptrine F (leu-F), exhibiting potent anti-inflammatory activity by modulating both innate and adaptive immune responses. Leu-F irreversibly binds to glyceraldehyde-3-phosphate dehydrogenase (GAPDH), a cross-kingdom glycolytic enzyme and a promising therapeutic target in autoimmune diseases. Crystal structure of the GAPDH-leu-F complex reveals the formation of a covalent bond between leu-F and the Cys152 residue. Leu-F notably attenuated glycolysis and concurrently diminished GAPDH-mediated stabilization of activated protein kinase B (AKT). Both leu-F and the total sesterterpenoid extract of Leucosceptrum canum demonstrated notable therapeutic efficacy and safety in mouse models of psoriasis and experimental autoimmune encephalomyelitis. This study underscores leu-F as a promising lead compound for autoimmune disease treatment and provides a compelling example of drug discovery inspired by chemical ecology.