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.

项目概要/摘要 蛋白质-蛋白质相互作用（PPI）涉及多种关键生物过程， 包括细胞增殖、生长、分化和凋亡。迄今为止，还没有通用的方法 调节胶原蛋白-蛋白质相互作用以及生物分子的许多基本方面 识别度仍未知。具体来说，胶原蛋白三螺旋和 蛋白质尚未完全表征或理解。我们最近发现胶原蛋白氮杂肽 其中至少一个α-碳原子已被氮取代，具有额外的链间 胶原蛋白三螺旋中的氢键，导致超稳定性和更有效的自组装。 因此，即使是短的胶原蛋白氮杂肽也能可靠地自组装成热稳定的三螺旋， 使它们成为新型三螺旋模拟物的有前途的选择。在这个项目中，我们建议使用 最少的氮杂肽来创建线性和环状胶原肽三螺旋模拟物。我们的具体目标 具体如下： 1) 胶原肽超稳定合成模拟物的合成和表征； 2） 合成并表征环状胶原肽三螺旋模拟物（CCP-mimics）； 3）表征 蛋白质相互作用我们的合成胶原蛋白肽。氮杂肽将使用固相合成 肽合成 (SPPS)，以便以精确的速度将氮杂氨基酸引入胶原蛋白主链中 位置并优化线性和环状肽的热力学稳定性。模块化的本质 我们的新胶原蛋白肽系统将提供高度可调的平台，任何生物 可以整合相关的蛋白质结合序列。我们的胶原蛋白肽模拟物将成为新的 用于了解胶原蛋白的基础生物学和生物化学的化学工具 相互作用组。拟议的研究最终可以作为通向未来的基础科学 病理学的生物医学治疗，其中精确调节胶原蛋白相互作用可以 显着提高患者的治疗效果。