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Organic Structure-directing Agent-free Synthesis for *BEA-type Zeolite Membrane
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Efficient Mining for Structurally Diverse Fusicoccane-Type Diterpenoids as Novel Antithrombotic Agents and Their
Alan Bao1, Xue Gong1, Shuang Lin1,2
1Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
Abstract:
Through genome mining, we discovered a 5/8/5 fusicoccane-type diterpenoid gene cluster (named Thm) from the biocontrol fungus Trichoderma harzianum, representing the first report of such a cluster in the genus Trichoderma. Heterologous expression of Thm in Aspergillus oryzae NSAR1 led to the isolation of 33 fusicoccane-type diterpenoids (including 30 new compounds 1-30). Structurally, compounds 1-14 were tetracyclic diterpenoids, with 1 and 2 being a class of rare fusicoccane-alkaloid hybrids. Mechanistic profiling revealed that compound 6 acts as a selective GPVI pathway antagonist, potently inhibiting Syk and PLCγ2 phosphorylation and subsequent platelet activation. In contrast, compound 31 exerts its antiplatelet effect via a distinct ROCK1-dependent pathway, suppressing cytoskeletal reorganization by reducing myosin light chain (MLC) phosphorylation and key regulator expression. Critically, both compounds demonstrate a groundbreaking therapeutic dissociation, providing robust protection against arterial and venous thrombosis without impairing normal hemostasis, thereby presenting a promising strategy for safe antithrombotic therapy.
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