Department of Chemistry, Purdue University, West Lafayette, Indiana 47907, United States.
Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, Indiana 47907, United States.
ACS Chem Biol. 2021 Nov 19;16(11):2604-2611. doi: 10.1021/acschembio.1c00641. Epub 2021 Oct 26.
Natural products are a bountiful source of bioactive molecules. Unfortunately, discovery of novel bioactive natural products is challenging due to cryptic biosynthetic gene clusters, low titers, and arduous purifications. Herein, we describe SNaPP (ynthetic tural roduct Inspired Cyclic eptides), a method for identifying NP-inspired bioactive peptides. SNaPP expedites bioactive molecule discovery by combining bioinformatics predictions of nonribosomal peptide synthetases with chemical synthesis of the predicted natural products (pNPs). SNaPP utilizes a recently discovered cyclase, the penicillin binding protein-like cyclase, as the lynchpin for the development of a library of head-to-tail cyclic peptide pNPs. Analysis of 500 biosynthetic gene clusters allowed for identification of 131 novel pNPs. Fifty-one diverse pNPs were synthesized using solid phase peptide synthesis and solution-phase cyclization. Antibacterial testing revealed 14 pNPs with antibiotic activity, including activity against multidrug-resistant Gram-negative bacteria. Overall, SNaPP demonstrates the power of combining bioinformatics predictions with chemical synthesis to accelerate the discovery of bioactive molecules.
天然产物是生物活性分子的丰富来源。然而，由于隐秘的生物合成基因簇、低产量和繁琐的纯化，新型生物活性天然产物的发现具有挑战性。本文中，我们描述了 SNaPP（合成天然产物启发的环肽），这是一种用于鉴定 NP 启发的生物活性肽的方法。SNaPP 通过将非核糖体肽合成酶的生物信息学预测与预测天然产物（pNP）的化学合成相结合，加速了生物活性分子的发现。SNaPP 利用最近发现的青霉素结合蛋白样环化酶作为开发头到尾环肽 pNP 文库的关键。对 500 个生物合成基因簇的分析允许鉴定 131 种新型 pNP。使用固相肽合成和溶液相环化合成了 51 种不同的 pNP。抗菌测试显示 14 种 pNP 具有抗菌活性，包括对多药耐药革兰氏阴性菌的活性。总体而言，SNaPP 证明了将生物信息学预测与化学合成相结合以加速生物活性分子发现的强大功能。
