Peptide Mimics of the Collagen Triple Helix

胶原三螺旋的肽模拟物

• 批准号: 10579283
• 负责人: David Michael Chenoweth
• 金额: $ 57.82万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10579283
• 关键词: Address; Amino Acid Substitution; Amino Acids; Apoptosis; Area; Behavior; Binding Proteins; Binding Sites; Biochemistry; Biological; Biological Assay; Biological Availability; Biological Process; Biology; Biophysics; Carbon; Cell Proliferation; Cell physiology; Cells; Chemicals; Chemistry; Collagen; Complement; Complex; Coupled; Crystallography; Cyclic Peptides; DDR2 gene; Data; Development; Diabetes Mellitus; Enzymes; Evaluation; Extracellular Matrix; Fibrosis; Future; Glycine; Goals; Growth; Health; Human; Human Biology; Hydrocarbons; Hydrogen Bonding; Individual; Interstitial Collagenase; Knowledge; Laboratories; Location; Malignant Neoplasms; Methods; Modification; Multiprotein Complexes; Nature; Neurodegenerative Disorders; Nitrogen; Pathology; Patient-Focused Outcomes; Peptide Synthesis; Peptides; Peptoids; Periodicity; Phase; Property; Proteins; Regulation; Resistance; Science; Solid; Structure; Surface; System; Therapeutic; Thermodynamics; Time; Vertebral column; X ray diffraction analysis; alpha helix; healing; improved; insight; interfacial; novel; novel therapeutics; peptidomimetics; protein aminoacid sequence; protein protein interaction; public health relevance; rational design; regenerative; response; scaffold; self assembly; synthetic peptide; thermostability; tool; triple helix; wound healing

Project Summary/Abstract Protein-protein interactions (PPIs) are involved in a diverse array of critical biological processes, including cell proliferation, growth, differentiation, and apoptosis. To date, there is no general way to modulate collagen protein-protein interactions, and many fundamental aspects of biomolecular recognition are still unknown. Specifically, numerous interactions between collagen triple helices and proteins are not fully characterized or understood. We have recently shown that collagen aza-peptides in which at least one alpha-carbon atom has been substituted with nitrogen, have additional interstrand hydrogen bonds in their collagen triple helix, resulting in hyperstability and more efficient self-assembly. As a result, even short collagen aza-peptides reliably self-assemble into thermostable triple helices, making them a promising choice for novel triple helix mimics. With this project, we propose to use minimal aza-peptides to create linear and cyclic collagen peptide triple helix mimics. Our specific aims are as follows: 1) Synthesize and characterize hyperstable synthetic mimics of collagen peptides; 2) Synthesize and characterize cyclic collagen peptide triple helix mimics (CCP-mimics); 3) Characterize protein interactions our synthetic collagen peptides. Aza-peptides will be synthesized using solid-phase peptide synthesis (SPPS) in order to introduce aza-amino acids into the collagen backbone at precise locations and optimize thermodynamic stability of the linear and cyclic peptides. The modular nature of our new collagen peptide systems will provide highly tunable platforms into which any biologically relevant protein binding sequence can be integrated. Our collagen peptide mimics will serve as new chemical tools for understanding the fundamental biology and biochemistry of the collagen-protein interactome. The proposed studies could ultimately serve as the fundamental science leading to future biomedical treatments for pathologies in which precisely modulating collagen-protein interactions could significantly enhance patient outcome.

项目摘要/摘要 蛋白质-蛋白质相互作用(PPI)涉及一系列不同的关键生物学过程， 包括细胞的增殖、生长、分化和凋亡。到目前为止，还没有通用的方法来 调节胶原蛋白与蛋白质的相互作用，以及生物分子的许多基本方面 人们对此的认可度仍不得而知。具体地说，胶原蛋白三螺旋之间的大量相互作用 蛋白质还没有得到充分的表征或理解。我们最近发现胶原蛋白氮杂肽 其中至少一个α-碳原子被氮取代，具有额外链间 它们的胶原蛋白三螺旋中存在氢键，导致超稳定性和更高效的自组装。 结果，即使是短的胶原氮杂多肽也可以可靠地自组装成耐热的三螺旋结构， 这使它们成为新的三螺旋模拟物的一个有前途的选择。在这个项目中，我们建议使用 最小氮杂多肽，以创建线性和环状胶原肽三螺旋模拟物。我们的具体目标 主要内容如下：1)合成和表征超稳定的胶原蛋白多肽模拟物；2) 环胶原肽三螺旋模拟物(CCP-模拟物)的合成与表征 蛋白质相互作用我们合成的胶原蛋白多肽。氮杂肽的合成将采用固相合成法 多肽合成(SPPS)，以精确地将氮杂氨基酸引入胶原骨架 并优化线状和环状多肽的热力学稳定性。的模块化特性 我们的新胶原蛋白多肽系统将提供高度可调的平台，任何生物 可以整合相应的蛋白质结合序列。我们的胶原肽模拟物将作为新的 了解胶原蛋白基本生物学和生物化学的化学工具 互动组。拟议的研究最终可能成为通向未来的基础科学。 精确调节胶原蛋白相互作用的病理生物医学治疗 显著提高患者的预后。