Phylogenomic Analysis of the Microviridin Biosynthetic Pathway Coupled with Targeted Chemo-Enzymatic Synthesis Yields Potent Protease Inhibitors
Phylogenomic Analysis of the Microviridin Biosynthetic Pathway Coupled with Targeted Chemo-Enzymatic Synthesis Yields Potent Protease Inhibitors
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DOI：
10.1021/acschembio.7b00124
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发表时间：
2017-06-01
影响因子：
4
通讯作者：
Fewer, David P.
中科院分区：
文献类型：
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作者：
Ahmed, Muhammad N.;Reyna-Gonzalez, Emmanuel;Fewer, David P.
天然产物及其半合成衍生物是制药工业药物的重要来源。细菌是天然产物的多产者，并且编码多种多样的天然产物生物合成基因簇。然而，这种多样性中的大部分是天然产品发现无法获得的。在这里，我们结合微病毒素生物合成途径的系统基因组分析和生物信息学预测的微病毒素的化学酶促合成来产生新的蛋白酶抑制剂。系统基因组学分析表明，microviridin生物合成基因簇发生在整个细菌结构域，编码三种不同的前体肽亚型。我们的分析揭示了microviridin生物合成的演变，并使其化学酶促生产的优先顺序。由蓝细菌Cyanothece sp. PCC 7822编码的四种microviridins的靶向一锅合成鉴定了一组新型且有效的丝氨酸蛋白酶抑制剂，其中最具活性的IC 50值为21.5 nM。这项研究推进了可用于天然产物发现的基因组挖掘技术，并消除了培养细菌的需要。
Natural products and their semisynthetic derivatives are an important source of drugs for the pharmaceutical industry. Bacteria are prolific producers of natural products and encode a vast diversity of natural product biosynthetic gene clusters. However, much of this diversity is inaccessible to natural product discovery. Here, we use a combination of phylogenomic analysis of the microviridin biosynthetic pathway and chemo-enzymatic synthesis of bioinformatically predicted microviridins to yield new protease inhibitors. Phylogenomic analysis demonstrated that microviridin biosynthetic gene clusters occur across the bacterial domain and encode three distinct subtypes of precursor peptides. Our analysis shed light on the evolution of microviridin biosynthesis and enabled prioritization of their chemo-enzymatic production. Targeted one-pot synthesis of four microviridins encoded by the cyanobacterium Cyanothece sp. PCC 7822 identified a set of novel and potent serine protease inhibitors, the most active of which had an IC50 value of 21.5 nM. This study advances the genome mining techniques available for natural product discovery and obviates the need to culture bacteria.