Reverse Biosynthesis: Generating Combinatorial Pools of Drug Leads from Enzyme-Mediated Fragmentation of Natural Products

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• 作者：Tomas Richardson-Sanchez ; Dr. William Tieu and Prof. Rachel Codd
• 刊名：ChemBioChem
• 出版年：2017
• 出版时间：February 16, 2017
• 年：2017
• 卷：18
• 期：4
• 页码：368-373
• 全文大小：803K
• ISSN：1439-7633

文摘

A combinatorial pool of hydroxamic acid fragments as potential metalloprotein drug leads was generated from the enzymatic hydrolysis of the natural product desferrioxamine B (DFOB). DFOB is a metabolite produced by Streptomyces pilosus for iron acquisition, and can be selectively catabolised by Niveispirillum irakense to access carbon for growth. The supernatant of a DFOB-supplemented culture of N. irakense was analysed by LC-MS at intervals over 168 h. This identified a mixture of endo-hydroxamic acid fragments that contained reactive terminal groups. The supernatants from two cultures (at 48 h and 168 h) were reacted with 1,8-naphthalic anhydride in a microwave synthesiser to generate pools of scriptaid analogues, which were screened against Zn^II-containing histone deacetylases (HDACs) and Fe^III-containing 5-lipoxygenase (5-LO). Compound S2 showed relative potency against 5-LO (IC₅₀=59 μm; BWA4C, 17 μm); it was 28-fold more selective towards 5-LO than HDAC1. Compound S1 inhibited HDAC1 but not 5-LO. Enzyme-mediated reverse biosynthesis could yield new benefits from structurally complex natural products in drug design.