Microbially Guided Discovery and Biosynthesis of Biologically Active Natural Products
Microbially Guided Discovery and Biosynthesis of Biologically Active Natural Products
复制标题
微生物引导的生物活性天然产物的发现和生物合成
DOI：
10.1021/acssynbio.1c00074
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发表时间：
2021
影响因子：
4.7
通讯作者：
Fox, Jerome M.
中科院分区：
文献类型：
--
作者：
Sarkar, Ankur;Kim, Edward Y.;Jang, Taehwan;Hongdusit, Akarawin;Kim, Hyungjun;Choi, Jeong-Mo;Fox, Jerome M.
抑制疾病相关蛋白的小分子的设计代表了药物化学的长期挑战。在这里，我们描述了一种方法，用于编码这一挑战-抑制人类药物靶标-进入微生物宿主，并使用它来指导发现和生物合成的目标，生物活性的天然产物。这种方法确定了两种以前未知的蛋白酪氨酸磷酸酶1B（PTP 1B）的萜类抑制剂，这是治疗糖尿病和癌症的一个难以捉摸的治疗靶点。这两种抑制剂似乎都靶向变构位点，这赋予了选择性，并且可以抑制活细胞中的PTP 1B。从4464个基因的库中筛选24个未表征的萜烯脱氢酶发现了额外的命中，证明了可扩展的发现方法，并且将不同的PTP掺入微生物宿主中产生了替代的PTP特异性检测系统。研究结果说明了利用微生物发现和构建天然产物的潜力，这些天然产物表现出精确定义的生化活性，但具有意想不到的结构和/或结合位点。
The design of small molecules that inhibit disease-relevant proteins represents a longstanding challenge of medicinal chemistry. Here, we describe an approach for encoding this challenge—the inhibition of a human drug target—into a microbial host and using it to guide the discovery and biosynthesis of targeted, biologically active natural products. This approach identified two previously unknown terpenoid inhibitors of protein tyrosine phosphatase 1B (PTP1B), an elusive therapeutic target for the treatment of diabetes and cancer. Both inhibitors appear to target an allosteric site, which confers selectivity, and can inhibit PTP1B in living cells. A screen of 24 uncharacterized terpene synthases from a pool of 4464 genes uncovered additional hits, demonstrating a scalable discovery approach, and the incorporation of different PTPs into the microbial host yielded alternative PTP-specific detection systems. Findings illustrate the potential for using microbes to discover and build natural products that exhibit precisely defined biochemical activities yet possess unanticipated structures and/or binding sites.