Bielicki John K
Donner Laboratory, Life Sciences Division, Lawrence Berkeley National Laboratory, University of California at Berkeley, Berkeley, California, USA.
Curr Opin Lipidol. 2016 Feb;27(1):40-6. doi: 10.1097/MOL.0000000000000258.
The review summarizes information pertaining to the preclinical development of new apolipoprotein (apo) E mimetic peptides that stimulate cellular cholesterol efflux.
Small α-helical peptides based on the C-terminal domain of apoE have been developed for therapeutic applications. These peptides stimulate cellular cholesterol efflux via the ATP-binding cassette transporter A1 (ABCA1) with high potency, like native apolipoproteins on a molar basis. This potent activity has been related to the unique ability of these peptides to maintain α-helix structure upon dilution. Recent structure-activity studies improving the safety features of these mimetic peptides have greatly improved their potential for clinical use. These studies have identified structural features of the class A α-helix motif that induce muscle toxicity and hypertriglyceridemia, which may have implications for the design of other HDL mimetic peptides.
ABCA1 is an integral membrane protein that plays a central role in biology. Its principal function is to mediate the efflux of cholesterol and phospholipid from cells to extracellular apo, preventing a build-up of excess cholesterol in membranes. This process generates HDL particles that perform a variety of functions to protect against disease. A number of these functions can be viewed as directly or indirectly supporting ABCA1 activity, thus constituting a positive feedback system to optimize cellular lipid efflux responses and disease prevention. Consequently, therapeutic approaches that mimic the activities of apos may prove highly effective to combat disease. One such approach involves the use of peptides. The broad biological relevance of ABCA1 suggests these apo mimetic peptides may be useful for the treatment of a number of diseases, such as atherosclerosis, diabetes, and Alzheimer's disease.
本综述总结了与刺激细胞胆固醇流出的新型载脂蛋白（apo）E模拟肽临床前开发相关的信息。
基于apoE C末端结构域的小α螺旋肽已被开发用于治疗应用。这些肽通过ATP结合盒转运蛋白A1（ABCA1）高效刺激细胞胆固醇流出，在摩尔基础上与天然载脂蛋白类似。这种强效活性与这些肽在稀释时维持α螺旋结构的独特能力有关。最近改善这些模拟肽安全特性的构效研究极大地提高了它们的临床应用潜力。这些研究确定了A类α螺旋基序的结构特征，这些特征会诱导肌肉毒性和高甘油三酯血症，这可能对其他高密度脂蛋白模拟肽的设计有影响。
ABCA1是一种整合膜蛋白，在生物学中起核心作用。其主要功能是介导胆固醇和磷脂从细胞向细胞外载脂蛋白的流出，防止膜中过量胆固醇的积累。这个过程产生执行多种功能以预防疾病的高密度脂蛋白颗粒。这些功能中的许多可以被视为直接或间接支持ABCA1活性，从而构成一个正反馈系统来优化细胞脂质流出反应和疾病预防。因此，模拟载脂蛋白活性的治疗方法可能被证明对对抗疾病非常有效。一种这样的方法涉及使用肽。ABCA1广泛的生物学相关性表明这些载脂蛋白模拟肽可能对治疗多种疾病有用，如动脉粥样硬化、糖尿病和阿尔茨海默病。
