Discovery of triterpenoids as potent dual inhibitors of pancreatic lipase and human carboxylesterase 1.
Discovery of triterpenoids as potent dual inhibitors of pancreatic lipase and human carboxylesterase 1.
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DOI：
10.1080/14756366.2022.2029855
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发表时间：
2022-12
影响因子：
5.6
通讯作者：
Yang L
中科院分区：
文献类型：
--
作者：
Zhang J;Pan QS;Qian XK;Zhou XL;Wang YJ;He RJ;Wang LT;Li YR;Huo H;Sun CG;Sun L;Zou LW;Yang L
胰脂肪酶（PL）是众所周知的预防和治疗肥胖的关键靶点。人羧酸酯酶1A （hCES1A）已成为治疗高脂血症的重要靶点。因此，基于PL和hCES1A的强效双靶点抑制剂的发现对于开发治疗相关代谢疾病的药物具有很大的潜力。本研究收集了一系列天然三萜，采用荧光生化法测定了这些三萜对PL和hCES1A的抑制作用。发现齐墩果酸（OA）和熊果酸（UA）对PL和hCES1A均有较好的抑制作用，且对hCES2A具有较高的选择性。随后，一些基于OA和UA骨架的化合物被合成和评估。这些化合物的构效关系（SAR）分析显示，UA C-3位点的乙酰基（化合物41）对PL和hCES1A的抑制都非常重要，IC50分别为0.75µM和0.014µM。此外，含有OA 2-烯醇和3-酮基团的化合物39对PL和hCES1A也有较强的抑制作用，IC50分别为2.13µM和0.055µM。此外，化合物39和41对hCES2A、丁酰胆碱酯酶（BChE）和二肽基肽酶IV （DPP-IV）等人丝氨酸水解酶具有较好的选择性。抑制动力学和分子对接研究表明，化合物39和41都是有效的PL混合抑制剂，而hCES1A的竞争抑制剂。进一步研究表明，化合物39和41均能抑制小鼠前脂肪细胞诱导的脂肪细胞成脂。总的来说，我们发现了两个对PL和hCES1A都有很强抑制能力的三萜衍生物，它们可以作为开发更有效的针对PL和hCES1A的双靶点抑制剂的有希望的先导化合物。
Pancreatic lipase (PL) is a well-known key target for the prevention and treatment of obesity. Human carboxylesterase 1A (hCES1A) has become an important target for the treatment of hyperlipidaemia. Thus, the discovery of potent dual-target inhibitors based on PL and hCES1A hold great potential for the development of remedies for treating related metabolic diseases. In this study, a series of natural triterpenoids were collected and the inhibitory effects of these triterpenoids on PL and hCES1A were determined using fluorescence-based biochemical assays. It was found that oleanolic acid (OA) and ursolic acid (UA) have the excellent inhibitory effects against PL and hCES1A, and highly selectivity over hCES2A. Subsequently, a number of compounds based on the OA and UA skeletons were synthesised and evaluated. Structure–activity relationship (SAR) analysis of these compounds revealed that the acetyl group at the C-3 site of UA (compound 41) was very essential for both PL and hCES1A inhibition, with IC50 of 0.75 µM and 0.014 µM, respectively. In addition, compound 39 with 2-enol and 3-ketal moiety of OA also has strong inhibitory effects against both PL and hCES1A, with IC50 of 2.13 µM and 0.055 µM, respectively. Furthermore, compound 39 and 41 exhibited good selectivity over other human serine hydrolases including hCES2A, butyrylcholinesterase (BChE) and dipeptidyl peptidase IV (DPP-IV). Inhibitory kinetics and molecular docking studies demonstrated that both compounds 39 and 41 were effective mixed inhibitors of PL, while competitive inhibitors of hCES1A. Further investigations demonstrated that both compounds 39 and 41 could inhibit adipocyte adipogenesis induced by mouse preadipocytes. Collectively, we found two triterpenoid derivatives with strong inhibitory ability on both PL and hCES1A, which can be served as promising lead compounds for the development of more potent dual-target inhibitors targeting on PL and hCES1A.
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