Tian Yongqi, Liu Cuicui, Wang Shaoyun, Du Ming, Zhu Beiwei
School of Food Science and Technology, National Engineering Research Center of Seafood, Dalian Polytechnic University, Dalian, China.
College of Biological Science and Engineering, Fuzhou University, Fuzhou, China.
Front Nutr. 2022 Aug 11;9:969558. doi: 10.3389/fnut.2022.969558. eCollection 2022.
Obesity has become an increasingly serious public health problem. Pancreatic lipase (PL) is identified as a ideal target for the prevention and treatment of obesity. Orlistat, the only approved PL inhibitor (PLI), is a powerful weight loss drug but has many side effects. Therefore, there is an urgent need to discover powerful PLIs with high safety. Protein hydrolysate has been demonstrated to be a treasure trove of PLIs, but recognizing responsible functional peptides from them is like looking for a needle in a haystack. In this work, we synthesized and optimized a PL ligand fishing model (PLLFM) using magnetic nanoparticles (MNPs), then PLLFM was used to quickly fish out potential PLIs from the Cod meat hydrolysate (CMH). Finally, two new PLIs, GSPPPSG and KLEGDLK were identified with IC of 0.60 and 1.08 mg/mL, respectively. The Lineweaver-Burk diagram showed that GSPPPSG is a non-competitively dominant mixed-type PLI, whereas KLEGDLK is a competitive inhibitory-type PLI. Moreover, molecular docking suggested that both peptides can stably bind to the key amino acid residues of the PL active site, mainly through hydrogen bonding, hydrophobic, and electrostatic interactions. In general, we not only established a method to rapidly fish out potential PLIs from protein hydrolysate, but also provided safe and efficient lead compounds for the development of novel diet foods or drugs.
肥胖已成为一个日益严重的公共卫生问题。胰腺脂肪酶（PL）被确定为预防和治疗肥胖的理想靶点。奥利司他是唯一被批准的PL抑制剂（PLI），是一种强效减肥药物，但有许多副作用。因此，迫切需要发现安全性高的强效PLI。蛋白质水解物已被证明是PLI的宝库，但从其中识别出起作用的功能肽犹如大海捞针。在这项工作中，我们使用磁性纳米颗粒（MNP）合成并优化了一种PL配体筛选模型（PLLFM），然后用PLLFM从鳕鱼鱼肉水解物（CMH）中快速筛选出潜在的PLI。最后，鉴定出两种新的PLI，GSPPPSG和KLEGDLK，其半数抑制浓度（IC）分别为0.60和1.08 mg/mL。Lineweaver - Burk图表明，GSPPPSG是一种非竞争性主导的混合型PLI，而KLEGDLK是一种竞争性抑制型PLI。此外，分子对接表明这两种肽都能稳定地结合到PL活性位点的关键氨基酸残基上，主要通过氢键、疏水和静电相互作用。总的来说，我们不仅建立了一种从蛋白质水解物中快速筛选潜在PLI的方法，还为新型减肥食品或药物的开发提供了安全有效的先导化合物。
