Small Molecule Receptors for Membrane Lipids

膜脂质小分子受体

• 批准号: 8530255
• 负责人: Jianmin Gao
• 金额: $ 24.77万
• 依托单位: BOSTON COLLEGE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8530255
• 关键词: Affinity; Affinity Chromatography; Aldehydes; Antibiotics; Apoptosis; Apoptotic; Bacteria; Binding; Binding Proteins; Biological; Biological Process; Boronic Acids; Case Study; Cell Death; Cell membrane; Cell surface; Cells; Characteristics; Charge; Chemical Structure; Chemicals; Chemistry; Code; Color; Complex; Cyclic Peptides; Development; Disease; Esters; Event; Funding; Glycols; Goals; Gramicidin; Head; Homeostasis; Image; Label; Lead; Libraries; Life; Ligands; Lipid Binding; Lipids; Liposomes; Lytic; Malignant Neoplasms; Mammalian Cell; Membrane; Membrane Lipids; Membrane Protein Traffic; Membrane Proteins; Methodology; Molecular; Molecular Weight; Morphogenesis; NMR Spectroscopy; Peptide Library; Peptide Receptor; Peptides; Phase; Phosphatidylglycerols; Phosphatidylserines; Phospholipids; Physiology; Property; Proteins; Regulation; Reporting; Research; Schiff Bases; Shapes; Site; Solid; Specificity; Structure; Testing; Time; Tissues; Toxin; Variant; amino group; base; crosslink; design; gramicidin A; improved; interest; membrane model; mutant; novel strategies; phosphatidylserine receptor; programs; receptor; scaffold; screening; small molecule; spatiotemporal; tool

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.

描述（由申请人提供）：膜脂质的小分子受体项目摘要细胞膜由多种脂质组成。很明显，它们不仅仅是细胞的物理障碍。相反，膜脂质的组成和分布在生理和疾病上具有显着的影响。例如，细菌和哺乳动物细胞在其质膜中显示出截然不同的组成，细菌膜含有很大一部分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仅限于质膜的内部小叶。 PS对细胞表面的外部化是凋亡的标志性事件，这是细胞死亡的主要机制。虽然我们开始欣赏脂质的意义，但在各种生物过程中的功能的复杂细节上仍有许多尚待发现。为此，识别特定脂质的小分子对于分析脂质的时空分布非常需要。我们假设小环状肽可以作为设计低分子量受体的有效且多功能的支架。我们的初步研究证明了这种方法的可行性：模仿天然蛋白乳肽蛋白（CLAC）的环状肽显示了PS的蛋白质样特异性，并有效地标记了凋亡细胞。本提交的目标1旨在进一步发展CLAC设计作为PS受体。我们将探索预科，多价和共价化学的潜力，以提高CLAC对PSSTESTESTEMBRANES的结合亲和力和特异性。使用CLAC肽作为蓝图，我们将设计循环肽的固相支持的库。筛选肽文库将使各种脂质的小分子受体能够发现。在该提案的目标2中，我们将扩展环状肽设计，以开发细菌脂质PG的配体。具体而言，我们将使用循环支架来显示通过共价化学结合PG头组的化学功能。靶向PG的能力将为设计膜 - 悠久抗生素的设计提供新的策略。