Small Molecule Receptors for Membrane Lipids

描述(申请人提供)：膜脂小分子受体项目摘要细胞膜由多种脂类组成。很明显，它们不仅仅是细胞的物理屏障。相反，膜脂的组成和分布对生理和疾病有重大影响。例如，细菌和哺乳动物细胞在其质膜上显示出截然不同的成分，细菌膜上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)，在健康的哺乳动物细胞中，它仅限于质膜的内叶。PS外化到细胞表面是细胞死亡的主要机制之一，是细胞凋亡的标志事件。虽然我们开始意识到脂类的重要性，但关于它们在各种生物过程中复杂的作用细节，仍有许多未被发现。为此，识别特定脂类的小分子对于描绘脂类的时空分布是非常可取的。我们推测，小环肽可以作为一种有效和通用的支架来设计低分子质量的膜脂受体。我们的初步研究证明了这种方法的可行性：模拟天然蛋白乳粘附素(CLAC)的环肽显示出PS的蛋白样特异性，并有效地标记凋亡细胞。本意见书的目标1旨在进一步开发作为PS受体的CLAC设计。我们将探索前组织、多价和共价化学的潜力，以提高CLAC与PS提呈膜的结合亲和力和特异性。以CLAC多肽为蓝本，我们将设计固相支撑的环多肽文库。多肽库的筛选将使各种脂质的小分子受体的发现成为可能。在本提案的目标2中，我们将扩展环肽的设计，以开发细菌脂蛋白PG的配体。具体地说，我们将使用环状支架展示通过共价化学结合PG头部基团的化学功能。靶向PG的能力将使设计膜裂解抗生素的新策略成为可能。 公共卫生相关性：膜脂小分子受体项目叙述脂质的组成和分布在生理学和疾病中具有重要意义。这项提议寻求开发针对细菌脂质磷脂酰甘油(PG)和细胞凋亡生物标记物磷脂酰丝氨酸(PS)的小分子。该计划的成功将导致开发抗癌抗生素和显像剂的新策略。

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.