Advancing the basic science of membrane permeability in macrocyclic peptides

推进大环肽膜渗透性的基础科学

• 批准号: 10552484
• 负责人: Robert SCOTT LOKEY
• 金额: $ 37.15万
• 依托单位: UNIVERSITY OF CALIFORNIA SANTA CRUZ
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2027-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10552484
• 关键词: Address; Antibodies; Basic Science; Behavior; Cell Membrane Permeability; Cells; Chemicals; Chromatography; DNA; Development; Drug Kinetics; Geometry; Goals; Lead; Libraries; Medicine; Membrane; Metabolism; Natural Products; Nature; Oral; Peptides; Permeability; Pharmaceutical Chemistry; Pharmaceutical Preparations; Positioning Attribute; Property; Proteins; Research; Side; Specificity; Technology; Vertebral column; absorption; analytical tool; inhibitor; lipophilicity; liver metabolism; member; natural product inspired; next generation sequencing; novel; programs; protein protein interaction; scaffold

Macrocyclic peptides (MCPs) can demonstrate antibody-like potency and specificity against "undruggable" targets such as protein-protein interactions. Some MPCs, especially ones found in nature, also have drug-like cell permeability and even oral absorption, leading to the proposition that MCPs define a fertile ground for the discovery of novel, cell permeable inhibitors against undruggable targets. My lab is among the leaders in the worldwide effort to define the factors that govern passive membrane permeability in MCPs. In addition to defining a set of rules for generating molecules in this space, we have shown that existing macrocyclic natural products represent only a tiny fraction of potential permeable scaffolds in this size range (MW 700-1500). As the basic science of membrane permeability in MCPs has continued to mature, new questions have arisen which our lab is uniquely positioned to address: To what extent can side chains sequester polar backbone atoms in the membrane, and, conversely, to what extent can polar side chain functionality be "smuggled" into the membrane via interactions with backbone atoms? Are there scaffold geometries that enhance these effects? What is the fundamental size limit to passive membrane permeability? To what extent can strongly ionizable groups be incorporated into lipophilic MCPs without abrogating permeability? Can DNA-encoded library technology be used to discover novel, membrane permeable scaffolds that greatly enhance the extent to which we can evaluate this chemical space, especially in the higher MW range? Our program will capitalize on recent developments in DNA-encoded library (DEL) technology to generate large (108 - 1012-member) libraries that are diversified at both the side chain and backbone levels. We have shown that DNA-conjugated MCPs can be separated chromatographically based on the permeability of the pendant macrocycle and independent of the encoding DNA molecule, allowing us to use the power of split-pool synthesis and next- generation sequencing to dramatically expand our ability to delineate the constraints on permeability among highly diverse scaffolds well above 1000 MW. Finally, there have been few systematic studies on the impact of scaffold geometry on efflux and hepatic metabolism, which, besides permeability, are important factors that govern pharmacokinetic behavior. We will utilize our powerful split-pool synthesis and MSMS-analytical tool to determine the effect of scaffold geometry on efflux and metabolism, which will further enhance our understanding of this important chemical space. This MIRA proposal seeks to build on a vibrant and successful research program to uncover the basic scientific principles governing drug-like properties in a chemical class that continues to inspire medicinal chemists in their pursuit of ever more challenging targets.

大环肽（MCP）可以表现出抗体样的效力和特异性， 例如蛋白质-蛋白质相互作用。一些MPC，特别是在自然界中发现的MPC，也具有药物样的 细胞渗透性，甚至口服吸收，导致主张MCP定义了肥沃的土壤， 发现新的细胞渗透性抑制剂，以对抗非药物靶点。我的实验室是世界上 世界范围内的努力，以确定因素，控制被动膜渗透性的MCP。除了 定义了一套规则，产生分子在这个空间，我们已经表明，现有的大环天然 在该尺寸范围内（MW 700-1500），产品仅代表潜在可渗透支架的一小部分。作为 MCP细胞膜渗透性的基础科学不断成熟，新的问题也不断出现 我们的实验室是唯一定位于解决：在多大程度上可以侧链螯合极性骨干 相反，在多大程度上可以将极性侧链功能“走私”到膜中， 通过与骨架原子的相互作用来破坏膜？是否有支架的几何形状， 影响？被动膜通透性的基本尺寸限制是什么？在多大程度上能够 可电离基团被纳入亲脂性MCP而不消除渗透性？DNA编码的 文库技术可用于发现新的、膜可渗透的支架， 我们可以评估这个化学空间，特别是在更高的MW范围？我们的计划将利用 关于DNA编码库（DEL）技术的最新发展，以产生大的（108 - 1012-成员） 在侧链和主链水平上都多样化的文库。我们已经证明，DNA结合 MCP可以基于侧链大环的渗透性进行色谱分离， 独立于编码DNA分子，允许我们使用分裂池合成的力量，然后- 代排序，以显着扩大我们的能力，划定之间的渗透性的限制 高度多样化的支架远高于1000 MW。最后，很少有系统的研究， 支架几何形状对流出和肝代谢的影响，除了渗透性之外， 控制药代动力学行为。我们将利用我们强大的分裂池合成和MSMS分析工具， 确定支架几何形状对流出和代谢的影响，这将进一步增强我们的 了解这个重要的化学空间。这MIRA建议旨在建立一个充满活力和成功的 一项研究计划，旨在揭示控制化学类药物性质的基本科学原理 这继续激励着药物化学家追求更具挑战性的目标。