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）：环肽已被探索作为针对多种生物靶标的配体。它们相对容易合成，同时表现出大多数其他类别的小分子无法比拟的复杂程度。然而，环肽通常具有较差的细胞渗透性，这是一般肽的共同特征。事实上，药物开发的一个关键瓶颈在于无法预测和控制控制小分子细胞通透性的因素。我们研究计划的全球目标是创造新一代具有生物活性、细胞可渗透性的环肽作为探针以及先导抗生素和抗真菌化合物。 在本提案中，我们试图通过测试有关主链构象、环大小和侧链功能对环肽被动膜扩散的影响的假设来扩大对这一类重要化合物的膜渗透性的理解。借鉴天然产物的经验，环肽的细胞渗透性通常由关键修饰决定，即一个或多个肽酰胺的 N-甲基化，这有助于将极性主链运输穿过疏水性脂质双层。 在这里，我们应用一种强大的新方法进行区域选择性 N-甲基化，以生成环肽文库，这些环肽文库比非甲基化对应物表现出更好的膜通透性。此外，我们将开发一种环状和线性肽的磺酰化策略，生成生物可逆的前药，相对于未修饰的母体化合物，其膜渗透性大大提高。最后，我们在酵母、细菌（霍乱弧菌）和哺乳动物细胞中进行了一系列高通量表型筛选，以寻找调节多种生物过程的化合物。 使用前三个目标中开发的方法，我们将生成受天然产物启发的膜可渗透环肽库，用于输入到这些筛选中，最终结果是一系列可供进一步开发的有效生物活性化合物。 公共健康相关性：我们研究计划的总体目标是了解小分子膜渗透性的结构基础。我们建议使用环肽作为分子支架来研究渗透性的构象基础，并应用我们所学到的知识来创建新一代生化探针。我们将计算方法与合成有机化学和高通量筛选相结合，开发出受天然产物启发的新型生物活性环肽。我们预计该项目将出现新的抗生素和抗真菌药物。