Cyclic peptide permeability

环肽通透性

• 批准号: 9895400
• 负责人: Robert SCOTT LOKEY
• 金额: $ 9.26万
• 依托单位: UNIVERSITY OF CALIFORNIA SANTA CRUZ
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-01 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9895400
• 关键词: Acetic Acids; Affinity; Amino Acids; Biochemical; Biological; Biological Availability; Biological Models; C-terminal; Cell Membrane Permeability; Cells; Chemicals; Collaborations; Complement; Computing Methodologies; Cyclic Peptides; Cyclosporine; DNA; Data Set; Diffusion; Elements; Exhibits; Future; High Pressure Liquid Chromatography; Hydrogen Bonding; Kinetics; Lead; Libraries; Lipid Bilayers; Liposomes; Membrane; Methods; Modeling; Molecular Conformation; Molecular Weight; N-terminal; Natural Products; Nucleic Acids; Oral; Penetration; Peptides; Permeability; Pharmaceutical Preparations; Phase; Phospholipids; Positioning Attribute; Property; Reporting; Scheme; Series; Side; Specificity; Structure; System; Techniques; Testing; Theoretical model; Therapeutic; Thermodynamics; Vertebral column; Water; base; computerized tools; deep sequencing; design; insight; lipophilicity; molecular dynamics; molecular size; novel; passive transport; protein protein interaction; scaffold; screening; small molecule; solute; stereochemistry; theories

Cyclic peptides can achieve exquisite biochemical potency and specificity against challenging targets such as protein-protein interactions (PPIs). Although the size and polarity of most cyclic peptides fail to meet Lipinski's "Rule of 5" for predicting drug-likeness, a growing number of cyclic peptides have been described that exhibit the ADME properties of small molecule drugs, including high passive cell permeability and oral bioavailability. These exceptional cases, which include natural products such as cyclosporine A (CSA) as well as a variety of model systems developed by our group, have generated enthusiasm for the idea that macrocycles may provide a “middle way” between small molecules and biologics in the pursuit of challenging intracellular targets. However, achieving drug-like permeability in cyclic peptides is far from straightforward. Simply removing the C- and N-termini alone is rarely sufficient for achieving therapeutically relevant cell permeability. Other factors combine to determine the properties of cyclic peptides, and my group has led the effort to elucidate principles that govern those properties. This proposal aims to 1) identify novel, lariat and stapled peptides that exhibit high passive membrane permeability; 2) develop selection strategies for filtering DNA-encoded libraries of cyclic peptides based on the net polarity of the pendant macrocycles; and 3) use NMR and computational methods to study the detailed mechanisms of permeability across model lipid bilayers. In Aim 1, we will synthesize mass-encoded libraries based on lariat and stapled peptide designs, and use methods developed in my group to evaluate their permeabilities en masse. The results will provide insights into structure-permeability relationships in this chemical space, as well as providing raw materials for the synthesis of libraries aimed at biochemical target-based screening. In Aim 2, we will begin by synthesizing a series of DNA-tagged cyclic peptide test systems in which the permeabilities of the pendant macrocycles, which differ only by stereochemistry at 2 positions, span nearly two log units. We will test a variety of separation schemes, some of which are known to separate nucleic acids based on the polarity of covalently attached small molecules. We will then synthesize a diverse library of ~108 lariat peptides and fractionate the library based on the intrinsic polarity of the attached peptides. Deep sequencing of the pre- and post-selection libraries will illuminate the “permeability landscape” in cyclic peptides in the 7-mer to 11-mer size range with unprecedented scope and breadth. In Aim 3, we will use 1H and 19F 2-D NMR techniques, combined with advanced molecular dynamics simulations performed by our collaborator, Prof. Sereina Riniker (ETH), to study the detailed mechanisms underlying passive membrane permeability in cyclic peptides. We will synthesize fluorinated derivatives of CSA and other model systems and study their transport kinetics across synthetic liposomes, and compare observations with current theoretical models.

循环petides可以实现针对挑战的独家生化效力和特异性 蛋白质 - 蛋白质相互作用（PPI）。尽管大多数环状胡椒的大小和极性无法满足Lipinski “ 5规则”用于预测毒品的毒品，已经描述了越来越多的环状宠物 小分子药物的ADME特性，包括高无源细胞渗透性和口服生物利用度。 这些特殊情况，包括天然产品，例如环孢素A（CSA）以及各种 我们小组开发的模型系统对大环可能的想法产生了热情 在追求挑战细胞内靶标时，提供小分子和生物制剂之间的“中间方式”。 然而，在环状宠物中实现类似药物的渗透性远非直接。只是删除c- 单独的N末端很少足以实现治疗相关的细胞渗透性。其他因素 结合以确定循环宠物的特性，我的小组领导了阐明原理的努力 管理这些属性。该提议的目的是1）确定退出的新颖，套索和分期的肽 高被动膜渗透性； 2）开发选择策略用于过滤DNA编码的库 基于吊坠大环的净极性的环状肽； 3）使用NMR和计算 研究模型脂质双层模型的详细机制的方法。在AIM 1中，我们将 基于套索和分期肽设计合成质量编码的库，并使用在中开发的方法 我的小组会评估他们的渗透率。结果将提供有关结构 - 渗透性的见解 在这个化学空间中的关系，并为综合库的合成提供了原材料 基于生化目标的筛查。在AIM 2中，我们将首先合成一系列DNA标记的循环 肽测试系统中吊坠大环的渗透率，仅由 立体化学在两个位置，跨越了几乎两个日志单元。我们将测试各种分离方案，其中一些 已知可以根据共同附着的小分子的极性分离核酸。我们 然后，将合成一个〜108个luariat辣椒的潜水库，并基于固有的库分馏 附着的辣椒的极性。预选库的深度测序将阐明 在7-Mer的循环petides中，“渗透率景观”具有前所未有的范围， 宽度。在AIM 3中，我们将使用1H和19F 2-D NMR技术，并结合先进的分子动力学 我们的合作者Sereina Riniker（ETH）进行的模拟研究了详细的机制 循环宠物中的潜在无源膜渗透性。我们将合成CSA的氟化衍生物 以及其他模型系统，并研究其跨合成脂质体的传输动力学，并比较 具有当前理论模型的观察。