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）可以证明对“不可能”的抗体样效力和特异性 诸如蛋白质蛋白质相互作用之类的靶标。一些MPC，尤其是在自然界中发现的MPC，也具有类似药物的 细胞渗透性甚至口服吸收，导致MCP定义了肥沃的地面的主张 发现新颖的细胞可渗透抑制剂对不良靶标的抑制剂。我的实验室是 在全球范围内努力定义了在MCPS中负责被动膜渗透性的因素。此外 定义在该空间中生成分子的一组规则，我们已经证明了现有的大环天然 产品仅占此尺寸范围内潜在可渗透脚手架的一小部分（MW 700-1500）。作为 MCP中膜渗透率的基础科学一直在成熟，新问题已经出现 我们的实验室独特地定位了：侧链在多大程度上可以隔离骨架骨架 膜中的原子，相反，极性侧链功能在多大程度上被“走私”到 通过与骨干原子相互作用的膜？是否有脚手架几何形状可以增强这些几何形状 效果？被动膜渗透性的基本尺寸限制是什么？在多大程度上可以强烈 可离子的组可将其纳入亲脂性MCP，而不会废除渗透性？ DNA可以编码 图书馆技术可用于发现新颖的膜可渗透脚手架，从而大大提高了程度 我们可以评估该化学空间，尤其是在较高的MW范围内？我们的计划将资本化 关于DNA编码图书馆（DEL）技术的最新发展，以生成大型（108-1012-MENT） 在侧链和主链水平上都有多样化的图书馆。我们已经表明DNA偶联 MCP可以根据吊坠大环的渗透性和 独立于编码DNA分子，使我们能够使用分裂池合成的能力和接下来的 生成测序以极大地扩大我们描述对渗透性约束的能力 高度多样的脚手架远高于1000兆瓦。最后，几乎没有关于影响的系统研究 外排和肝代谢的脚手架几何形状，除了渗透性外，这是重要因素 控制药代动力学行为。我们将利用强大的分裂池合成和MSMS分析工具 确定支架几何形状对外排和代谢的影响，这将进一步增强我们 了解这个重要的化学空间。这个Mira提议旨在建立在充满活力和成功的基础上 研究计划，以揭示化学类别中类似药物的特性的基本科学原理 这继续激发医学化学家追求更具挑战性的目标。