The development of gut microbiota‐targeted small molecules represents a promising platform for the identification of new therapeutics based on the implication of human gut bacteria with different diseases. Bacterial trimethylamine (TMA)‐lyase (CutC) is expressed in gut bacteria and catalyzes the conversion of choline to TMA. The association of elevated TMA production with various disorders has directed research efforts toward identification of CutC inhibitors. Herein, we introduce peptidomimetics as a promising toolbox for the discovery of CutC inhibitors. Our approach starts with screening a library of peptidomimetics for intestinal metabolic stability followed by in vitro CutC inhibition. Compound 5 was identified from this screening platform with IC₅₀ value of 5.9 ± 0.6 μM for CutC inhibition. Unlike previously reported CutC inhibitors, compound 5 possessed universal CutC inhibitory activity in different bacterial strains. Molecular dynamics simulations suggested a plausible binding site and inhibition mechanism for compound 5. Therefore, compound 5 is a promising lead for further structural optimization in the search for CutC‐targeted small molecules.

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基于肽模拟物的微生物三甲胺裂解酶抑制剂方法

肠道微生物群靶向小分子的开发代表了一个有前景的平台，可以根据人类肠道细菌对不同疾病的影响来鉴定新的治疗方法。细菌三甲胺 (TMA)-裂解酶 (CutC) 在肠道细菌中表达并催化胆碱转化为 TMA。升高的 TMA 产生与各种疾病的关联已将研究工作导向 CutC 抑制剂的鉴定。在此，我们介绍肽模拟物作为发现 CutC 抑制剂的有前途的工具箱。我们的方法从筛选具有肠道代谢稳定性的肽模拟物库开始，然后进行体外 CutC 抑制。从该筛选平台中鉴定出化合物5，IC ₅₀CutC 抑制的值为 5.9 ± 0.6 μM。与之前报道的 CutC 抑制剂不同，化合物5在不同的细菌菌株中具有通用的 CutC 抑制活性。分子动力学模拟表明化合物5具有合理的结合位点和抑制机制。因此，化合物5是寻找 CutC 靶向小分子的进一步结构优化的有希望的先导。