Small Molecule Receptors for Membrane Lipids

描述（由申请人提供）：膜脂类小分子受体项目概述细胞膜由多种脂类组成。很明显，它们不仅仅是作为细胞的物理屏障。相反，膜脂的组成和分布对生理和疾病有重要的影响。例如，细菌和哺乳动物细胞在质膜中显示出显著不同的成分，细菌膜中含有很大比例的带负电荷的磷脂酰甘油（PG）。另一个众所周知的例子是磷脂酰丝氨酸（PS），它在健康的哺乳动物细胞中完全局限于质膜的内小叶。PS外化到细胞表面是细胞凋亡的标志事件，是细胞死亡的主要机制。虽然我们开始认识到脂质的重要性，但它们在各种生物过程中功能的复杂细节仍有待揭示。为此，识别特定脂质的小分子对于分析脂质的时空分布是非常理想的。我们假设小环肽可以作为设计膜脂低分子量受体的有效和通用的支架。我们的初步研究证明了这种方法的可行性：模拟天然蛋白乳酸粘附素（cLac）的环肽对PS表现出蛋白样特异性，并有效地标记凋亡细胞。本申请的目标1寻求进一步发展cLac设计作为PS受体。我们将探索预组织、多价和共价化学的潜力，以提高cLac对ps呈递膜的结合亲和力和特异性。以cLac肽为蓝本，我们将设计固相支持的环肽文库。肽库的筛选将有助于发现各种脂质的小分子受体。在本提案的目标2中，我们将扩展环肽设计以开发细菌脂质PG的配体。具体来说，我们将使用环支架来展示通过共价化学结合PG头基的化学功能。靶向PG的能力将为膜溶性抗生素的设计提供新的策略。

DESCRIPTION (provided by applicant): Small Molecule Receptors for Membrane Lipids Project Summary Cell membranes consist of a variety of lipids. It is clear that they do not simply serve as a physical barrier of a cell. Instead the composition and distribution of membrane lipids have significant ramifications for physiology and disease. For example, bacterial and mammalian cells display dramatically different compositions in their plasma membranes, with bacterial membrane harboring a large percentage of the negatively charged phosphatidylglycerol (PG). Another well known example is phosphatidylserine (PS), which in healthy mammalian cells is exclusively confined to the inner leaflet of the plasma membrane. Externalization of PS to the cell surface is a hallmark event of apoptosis, a primary mechanism of cell death. While we begin to appreciate the significance of lipids, much remains to be uncovered on the intricate details of their function in a variety of biological processes. Toward this end, small molecules that recognize a specific lipid are highly desirable for profiling the spatiotemporal distribution of lipids. We hypothesize that small cyclic peptides could serve as an effective and versatile scaffold for designing low molecular weight receptors for membrane lipids. Our preliminary studies demonstrated the feasibility of this approach: cyclic peptides mimicking the natural protein lactadherin (cLac) display protein-like specificity for PS and effectively label apoptotic cells. Aim 1 of this submission seeks to further develop the cLac design as PS receptors. We will explore the potential of pre- organization, polyvalency and covalent chemistry to improve the binding affinity and specificity of cLac towards PS-presenting membranes. Using the cLac peptide as a blueprint, we will design solid phase supported libraries of cyclic peptides. Screening of the peptide libraries will enable discovery of small molecule receptors for a variety of lipids. In aim 2 of this proposal, we will expand the cyclic peptide design to develop ligands for the bacterial lipid PG. Specifically, we will use the cyclic scaffold to display chemical functionalities that bind PG head groups through covalent chemistry. The capability of targeting PG will enable novel strategies for the design of membrane-lytic antibiotics. PUBLIC HEALTH RELEVANCE: Small Molecule Receptors for Membrane Lipids Project Narrative Lipid composition and distribution have significant implications in physiology and disease. This proposal seeks to develop small molecules that target the bacterial lipid phosphatidylglycerol (PG) and the apoptosis biomarker phosphatidylserine (PS). Success of this program will lead to novel strategies for developing antibiotics and imaging agents for cancer.