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

IF 11.7 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Science Advances Pub Date : 2025-07-25 DOI:10.1126/sciadv.adw2578

Ting-Ting Zhou, Yu Zheng, Man-Wen Zhang, Li-Hu Gong, Kai Guo, Xiao-Ping He, Yan-Chun Liu, Jonathan Gershenzon, Yan Liu, Sheng-Hong Li

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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.

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植物防御导向的天然抗银屑病剂靶向GAPDH的发现

阐明天然产物在植物适应机制中的生态功能是发现先导化合物的一种新兴手段。在这里，我们展示了一种未描述的植物腺体毛状体特异性防御酯萜类，亮氨酸F（亮氨酸F），通过调节先天和适应性免疫反应表现出有效的抗炎活性。亮氨酸- f不可逆地结合甘油醛-3-磷酸脱氢酶（GAPDH），这是一种跨界糖酵解酶，也是自身免疫性疾病的一个有希望的治疗靶点。GAPDH-leu-F配合物的晶体结构揭示了leu-F与Cys152残基之间形成共价键。Leu-F显著减弱糖酵解，同时减弱gapdh介导的活化蛋白激酶B （AKT）的稳定性。在银屑病和实验性自身免疫性脑脊髓炎小鼠模型中，银屑病f和银屑病总酯萜提取物均显示出显著的疗效和安全性。这项研究强调了leu-F作为一种有前途的自身免疫性疾病治疗先导化合物，并提供了一个受化学生态学启发的药物发现的引人注目的例子。

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来源期刊

Science Advances 综合性期刊-综合性期刊

CiteScore

21.40

自引率

1.50%

发文量

1937

审稿时长

29 weeks

期刊介绍： Science Advances, an open-access journal by AAAS, publishes impactful research in diverse scientific areas. It aims for fair, fast, and expert peer review, providing freely accessible research to readers. Led by distinguished scientists, the journal supports AAAS's mission by extending Science magazine's capacity to identify and promote significant advances. Evolving digital publishing technologies play a crucial role in advancing AAAS's global mission for science communication and benefitting humankind.