Chemistry, Indian Institute of Technology Gandhinagar, Palaj, Gandhinagar, 382355, India.
Shobhaben Pratapbhai Patel School of Pharmacy & Technology Management, SVKM's NMIMS, V.L. Mehta Road, Vile Parle (W), Mumbai, 400056, India.
Sci Rep. 2019 Jan 17;9(1):190. doi: 10.1038/s41598-018-37490-x.
Helicobacter pylori (H. pylori), the major cause of several gastric disorders has been recognied as a type I carcinogen. By virtue of resistance developed by H. pylori strains, currently used antibiotic based treatments rather demonstrate high failure rates. Hence, there is an emerging need for identification of new targets to treat H. pylori infection. Inosine-5'-monophosphate dehydrogenase (IMPDH) has been studied as a potential target to treat H. pylori infection. Here, a detailed enzyme kinetic study of recombinant expressed H. pylori inosine-5'-monophosphate dehydrogenase (HpIMPDH) is presented. A new in-house synthesized indole-based scaffold is identified as an inhibitor for HpIMPDH. These indole-based compounds showed non-competitive inhibition against IMP and NAD whereas the benzimidazole compounds were found be uncompetitive inhibitors. The new indole scaffold ensures specificity due to its high selectivity for bacterial IMPDH over human IMPDH II. Our work aims to overcome the drawback of existing inhibitors by introducing new indole scaffold for targeting bacterial IMPDH.
幽门螺杆菌（H. pylori）是多种胃部疾病的主要原因，已被确认为 I 类致癌物。由于 H. pylori 菌株产生的耐药性，目前使用的基于抗生素的治疗方法显示出较高的失败率。因此，迫切需要确定新的靶点来治疗 H. pylori 感染。肌苷-5'-单磷酸脱氢酶（IMPDH）已被研究作为治疗 H. pylori 感染的潜在靶点。在此，呈现了重组表达的幽门螺杆菌肌苷-5'-单磷酸脱氢酶（HpIMPDH）的详细酶动力学研究。鉴定出一种新的合成的吲哚基支架作为 HpIMPDH 的抑制剂。这些吲哚基化合物对 IMP 和 NAD 表现出非竞争性抑制，而苯并咪唑化合物则被发现是竞争性抑制剂。新的吲哚支架由于其对细菌 IMPDH 相对于人 IMPDH II 的高选择性，确保了特异性。我们的工作旨在通过引入针对细菌 IMPDH 的新吲哚支架来克服现有抑制剂的缺点。
