A target and efficient synthetic strategy for structural and bioactivity optimization of a fungal natural product
A target and efficient synthetic strategy for structural and bioactivity optimization of a fungal natural product
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真菌天然产物结构和生物活性优化的目标高效合成策略
DOI：
10.1016/j.ejmech.2021.114067
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发表时间：
2022-02-05
影响因子：
6.7
通讯作者：
Mao, Xu-Ming
中科院分区：
文献类型：
--
作者：
Cao, Fei;Zhang, Min-Kui;Mao, Xu-Ming
药物在很大程度上受到天然产物的启发，而其生物合成基础的酶使其具有复杂的结构和多种生物活性。尽管如此，高酶特异性和有限的体内前体类型限制了天然产物的储存库，但自然界已经将天然产物与活性位点印迹，这些活性位点可以通过化学合成容易地修饰各种官能团以获得更有利的可药用性。在这里，在较少开发的真菌天然产物中，我们引入CtvA，一种用于曲霉属中真菌毒素黄绿青霉素生物合成的聚酮合酶，到内生真菌Calcarisporium arbuscula中，以基于aurovertin生物合成酶的多功能性和混杂性将四氢呋喃（THF）扩展到二氧杂双环辛烷（DBO）环部分中。通过化学合成对细胞毒性至关重要的羟基上的替代酰化产生具有改善的抗肿瘤活性和药代动力学的化合物。因此，我们展示了一种有效的策略方法，以有效地优化真菌天然产物，以获得更有前途的药物开发。nbsp;（c）2021 Elsevier Masson SAS。All rights reserved.
Drugs have been largely inspired from natural products, while enzymes underlying their biosynthesis have enabled complex structures and diverse bioactivities. Nevertheless, the high enzyme specificity and limited in vivo precursor types have restricted the natural product reservoir, but Nature has imprinted natural products with active sites, which can be readily modified by chemosynthesis with various functional groups for more favorable druggability. Here in the less exploited fungal natural products, we introduced CtvA, a polyketide synthase for a mycotoxin citreoviridin biosynthesis in Aspergillus, into an endophytic fungus Calcarisporium arbuscula to expand tetrahydrofuran (THF) into a dioxabicyclo-octane (DBO) ring moiety based on versatility and promiscuity of the aurovertin biosynthetic enzyme. Alternative acylations on the hydroxyl groups essential for cell toxicity by chemosynthesis produced compounds with improved anti-tumor activities and pharmacokinetics. Thus, we showed an effective strategic way to optimize the fungal natural product efficiently for more promising drug development.& nbsp;(c) 2021 Elsevier Masson SAS. All rights reserved.