Synthesis and discovery of biologically active cell-permeable cyclic peptides

生物活性细胞渗透性环肽的合成和发现

• 批准号: 7898759
• 负责人: Robert SCOTT LOKEY
• 金额: $ 30.82万
• 依托单位: UNIVERSITY OF CALIFORNIA SANTA CRUZ
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-29 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7898759
• 关键词: Accounting; Affinity; Age; Amides; Antibiotics; Antifungal Agents; Antifungal Antibiotics; Bacteria; Biochemical; Biological; Biological Assay; Biological Factors; Biological Process; Cell Membrane Permeability; Cells; Characteristics; Chemical Models; Collection; Cyclic Peptides; Development; Diffusion; Exhibits; Generations; Hydrogen; Lead; Learning; Libraries; Ligands; Lipid Bilayers; Mammalian Cell; Membrane; Methods; Methylation; Modification; Molecular; Molecular Conformation; Nuts; Organic Chemistry; Parents; Peptides; Permeability; Phenotype; Prodrugs; Relative (related person); Research; Side; Testing; Time; Vertebral column; Vibrio cholerae; Yeasts; base; drug development; high throughput screening; improved; novel strategies; programs; public health relevance; scaffold; small molecule

DESCRIPTION (provided by applicant): Cyclic peptides have been explored as ligands against a wide variety of biological targets. They are relatively easy to synthesize, and, at the same time, exhibit a degree of complexity unrivaled by most other classes of small molecules. However, cyclic peptides often suffer from poor cell permeability, a characteristic common to peptides in general. Indeed, a key bottleneck in drug development lies in the inability to predict and control factors that govern cell permeability in small molecules. The global objective of our research program is to create a new generation of biologically active, cell permeable cyclic peptides as probes and lead antibiotic and antifungal compounds. In this proposal, we seek to broaden our understanding of membrane permeability in this important class of compounds by testing hypotheses regarding the influence on backbone conformation, ring size, and side chain functionality, on the passive membrane diffusion of cyclic peptides. Taking a lesson from natural products, cell permeability in cyclic peptides is often determined by key modification - namely, N-methylation of one or more peptide amides - that help to transport the polar backbone across the hydrophobic lipid bilayer. Here we apply a powerful new approach to regioselective N-methylation to generate libraries of cyclic peptides that exhibit improved membrane permeability over their non-methylated counterparts. In addition, we will develop a strategy for the sulfenylation of cyclic and linear peptides, generating bioreversible prodrugs with greatly improved membrane permeability relative to their unmodified parent compounds. Finally, we have put in place a panel of high-throughput phenotypic screens in yeast, bacteria (V. cholera), and mammalian cells for compounds that modulate a wide variety of biological processes. Using the methods developed in the first three aims, we will generate libraries of natural product-inspired, membrane permeable cyclic peptides for input into these screens, with the end result being a collection of potent bioactive compounds poised for further development. PUBLIC HEALTH RELEVANCE: The overall objective of our research program is to understand the structural basis of membrane permeability in small molecules. We propose to use cyclic peptides as molecular scaffolds to study the conformational basis of permeability, and apply what we learn to create a new generation of biochemical probes. We combine computational approaches with synthetic organic chemistry and high-throughput screening to develop a new class of bioactive cyclic peptides inspired by natural products. We expect that new antibiotics and antifungal agents will emerge from this project.

描述（由申请人提供）：已经探索了针对各种生物学靶标的配体探索。它们相对易于合成，同时表现出大多数其他类别的小分子无与伦比的复杂程度。然而，环状肽通常会遭受细胞渗透性差，这通常是肽常见的特征。实际上，药物开发中的关键瓶颈在于无法预测和控制小分子中细胞渗透性的因素。我们的研究计划的全球目标是创建新一代的生物活性，可渗透的细胞循环肽作为探针和铅抗生素和抗真菌化合物。 在该提案中，我们试图通过测试有关对骨架构象，环大小和侧链功能的影响的假设，以扩大对这种重要化合物中膜通透性的理解，对环状肽的被动膜扩散。从天然产物中汲取教训，通常通过关键修饰（即，一个或多个肽酰胺的N-甲基化）确定环状肽中的细胞渗透性 - 有助于将极性骨架在疏水性脂质双层中运输。 在这里，我们将一种强大的新方法用于区域选择性N-甲基化，以生成环状肽的库，这些肽在非甲基化对应物上表现出改善的膜渗透性。此外，我们还将制定一种策略，以旋转环肽和线性肽的磺酰化，从而产生具有相对于其未修饰的母体化合物的膜渗透性的生物可烘烤前药。最后，我们在酵母，细菌（V.霍乱）和哺乳动物细胞中为调节各种生物学过程的化合物提供了一组高通量表型筛选。 使用前三个目标中开发的方法，我们将生成自然产品启发的膜渗透循环肽的库，以输入这些筛选，最终结果是收集了有效的生物活性化合物，该化合物有望进一步开发。 公共卫生相关性：我们的研究计划的总体目标是了解小分子中膜渗透性的结构基础。我们建议将环状肽用作分子支架来研究渗透性的构象基础，并应用我们学会的东西来创建新一代的生化探针。我们将计算方法与合成有机化学和高通量筛选相结合，以开发出受天然产物启发的新的生物活性环状肽。我们预计该项目将出现新的抗生素和抗真菌剂。