Plant defense-directed discovery of a natural anti-psoriasis agent targeting GAPDH.

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 Cys(152) 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.