Gou Sanhu, Wang Li, Zhong Chao, Chen Xinyue, Ouyang Xu, Li Beibei, Bao Guangjun, Liu Hui, Zhang Yun, Ni Jingman
Institute of Pharmaceutics, School of Pharmacy, Lanzhou University, Lanzhou, China.
Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China.
Br J Pharmacol. 2020 Oct;177(20):4627-4644. doi: 10.1111/bph.15213. Epub 2020 Sep 9.
Apolipoprotein A-I (apoA-I) mimetic peptides (AAMPs) are short peptides that can mimic the physiological effects of apoA-I, including the suppression of atherosclerosis by reversely transporting peripheral cholesterol to the liver. As the hydrophobicity of apoA-I is considered important for its lipid transport, novel AAMPs were designed and synthesized in this study by gradually increasing the hydrophobicity of the parent peptide, and their anti-atherosclerotic effects were tested.
Seventeen new AAMPs (P1-P17) with incrementally increased hydrophobicity were designed and synthesized by replacing the amino acids 221-240 of apoA-I (VLESFKVSFLSALEEYTKKL). Their effects on cholesterol efflux were evaluated. Their cytotoxicity and haemolytic activity were also measured. The in vitro mechanism of the action of the new peptides was explored. Adult apolipoprotein E mice were used to evaluate the anti-atherosclerotic activity of the best candidate, and the mechanistic basis of its anti-atherosclerotic effects was explored.
Seventeen new AAMPs (P1-P17) were synthesized, and their cholesterol efflux activity and cytotoxicity were closely related to their hydrophobicity. P12 (FLEKLKELLEHLKELLTKLL) was the best candidate and most strongly promoted cholesterol efflux among the non-toxic peptides (P1-P12). With its phospholipid affinity, P12 facilitated cholesterol transport through the ATP-binding cassette transporter A1. In vivo, P12 exhibited prominent anti-atherosclerotic activity via coupling with HDL.
P12 featured adequate hydrophobicity, which ensured its efficient binding with cytomembrane phospholipids, cholesterol and HDL, and provided a basis for its ability to reversely transport cholesterol and treat atherosclerosis.
载脂蛋白A-I（apoA-I）模拟肽（AAMPs）是一类短肽，可模拟apoA-I的生理作用，包括通过将外周胆固醇逆向转运至肝脏来抑制动脉粥样硬化。由于apoA-I的疏水性被认为对其脂质转运很重要，本研究通过逐步增加母肽的疏水性设计并合成了新型AAMPs，并测试了它们的抗动脉粥样硬化作用。
通过替换apoA-I的221-240位氨基酸（VLESFKVSFLSALEEYTKKL）设计并合成了17种疏水性递增的新型AAMPs（P1-P17）。评估了它们对胆固醇流出的影响。还测量了它们的细胞毒性和溶血活性。探索了新肽作用的体外机制。使用成年载脂蛋白E小鼠评估最佳候选物的抗动脉粥样硬化活性，并探索其抗动脉粥样硬化作用的机制基础。
合成了17种新型AAMPs（P1-P17），它们的胆固醇流出活性和细胞毒性与其疏水性密切相关。P12（FLEKLKELLEHLKELLTKLL）是最佳候选物，在无毒肽（P1-P12）中最强烈地促进胆固醇流出。凭借其对磷脂的亲和力，P12促进胆固醇通过ATP结合盒转运蛋白A1转运。在体内，P12通过与高密度脂蛋白（HDL）结合表现出显著的抗动脉粥样硬化活性。
P12具有足够的疏水性，确保其与细胞膜磷脂、胆固醇和HDL有效结合，为其逆向转运胆固醇和治疗动脉粥样硬化的能力提供了基础。
