Download MendeleyPlant defense-directed discovery of a natural anti-psoriasis agent targeting GAPDH.
Zhou, T.T., Zheng, Y., Zhang, M.W., Gong, L.H., Guo, K., He, X.P., Liu, Y.C., Gershenzon, J., Liu, Y., Li, S.H.(2025) Sci Adv 11: eadw2578-eadw2578
- PubMed: 40712011
- DOI: https://doi.org/10.1126/sciadv.adw2578
- Primary Citation of Related Structures:
9L3E - PubMed 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 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.
- State Key Laboratory of Phytochemistry and Natural Medicines, and Yunnan Key Laboratory of Natural Medicinal Chemistry, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, P. R. China.
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