Evolving New Glycosaminoglycan Mimetics

不断发展的新糖胺聚糖模拟物

基本信息

批准号：
10217188
负责人：
Linda C Hsieh-Wilson
金额：
$ 38.42万
依托单位：
CALIFORNIA INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-25 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10217188
关键词：
3-Dimensional Affinity Alzheimer&apos s Disease Anti-Inflammatory Agents Anticoagulants Antithrombin III Architecture Autoimmune Diseases Avidity Binding Binding Proteins Binding Sites Biological Process Biological Response Modifiers Blood coagulation CXCL10 gene CXCL11 gene CXCL9 gene CXCR3 gene Cell Proliferation Cell division Cells Chemicals Chemotaxis Chondroitin Sulfates Collaborations Communicable Diseases Consumption Dementia Development Directed Molecular Evolution Disaccharides Disease Drug Targeting Epitopes Event FGF2 gene Glycopeptides Glycosaminoglycans Goals Growth Factor HIV Heparin Heparitin Sulfate Immune response In Vitro Individual Inflammation Inflammation Mediators Inflammatory Laboratories Lead Libraries Macular degeneration Malignant Neoplasms Mediating Messenger RNA Methods Microtubule-Associated Proteins Neoplasm Metastasis Nerve Degeneration Neurodegenerative Disorders Neurons Oligosaccharides Parkinson Disease Pathogenesis Pathogenicity Pathologic Pathologic Processes Pathology Peptides Pharmaceutical Preparations Physiological Physiological Processes Play Polymers Polysaccharides Proteins RANTES Research Role Sampling Signal Pathway Signal Transduction Signaling Protein Structure Structure-Activity Relationship Sulfate Testing Therapeutic Therapeutic Studies Time Translations Variant Work angiogenesis base cell motility chemokine human disease immunoregulation in vivo insight interest link protein migration mimetics monomer nanomolar neurodevelopment neuronal growth neutralizing antibody novel novel strategies novel therapeutic intervention novel therapeutics pathogen polymerization preference protein aminoacid sequence protein complex receptor scaffold stem tau Proteins tau interaction tool transmission process uptake wound healing

项目摘要

Project Summary Glycosaminoglycans (GAGs) play important roles in many physiological and pathological events such as cell division, inflammation, neural development, and cancer metastasis. The long polysaccharide chains of GAGs contain various sulfated disaccharides that are organized into sulfate-rich and under-sulfated domains. This rich structural diversity enables GAGs such as heparan sulfate (HS) to interact with numerous proteins and regulate key signaling pathways. However, efforts to understand their structure-function relationships and harness their therapeutic potential have been hampered by the chemical complexity of GAGs and a lack of tools. At present, there are no tools to manipulate the interactions of GAGs with specific proteins of interest, thus complicating efforts to pinpoint their precise roles. The goal of this project is to develop novel chemical probes for selectively modulating GAG activity. We will use a directed evolution-based approach to create a new class of GAG mimetics – multivalent glycopeptides appended with short, active HS motifs – to modulate specific HS-protein interactions. Random sampling of peptide sequences by directed evolution should allow for the selection of structures containing the ideal number and arrangement of HS motifs. In addition to optimal HS clustering, selected peptides should contain peptide motifs recognized by the protein of interest, thus generating highly specific GAG probes. In Aim 1, we will work in collaboration with the Krauss laboratory to develop the approach and generate HS mimetics that interact selectively with fibroblast growth factor 2 (FGF2), a key growth factor involved in cell migration, angiogenesis, and differentiation. In Aim 2, we will evolve glycopeptides that bind to specific forms of tau, a microtubule-associated protein linked to dementias such as Alzheimer's disease and Parkinson's disease. We will use these HS mimetics to understand the mechanisms underlying tau uptake into neurons and neurodegeneration. In addition, we will explore whether our mimetics can block the intercellular spreading of tau and its pathogenic consequences. In Aim 3, we will evolve glycopeptides that bind chemokines (specifically CXCL9, CXCL10 and CXCL11), a class of therapeutically important proteins that are key mediators of inflammation. Our probes should provide unique insights into the paradoxical functional redundancy of chemokines, enabling us to tease apart their individual roles. Together, these studies will produce a novel class of GAG-based probes for understanding the physiological functions of GAGs and may ultimately lead to new therapeutic leads or approaches to diseases such as cancer, neurodegenerative diseases, inflammatory and autoimmune disorders, and infectious diseases.

项目摘要糖胺聚糖（插科打）在许多物理和病理事件中起重要作用例如细胞分裂，感染，神经发育和癌症转移。长插孔的多糖链包含各种硫化二糖，这些二糖被组织到富含硫酸盐和硫酸盐不足的结构域。这种丰富的结构多样性使得诸如硫酸乙酰肝素（HS）与许多蛋白质相互作用并调节钥匙信号通路。但是，努力了解他们的结构功能关系并利用他们的治疗潜力受到堵嘴的化学复杂性的阻碍，缺乏工具。目前，没有工具可以操纵插科打与特定蛋白质的相互作用感兴趣的，因此使精确角色的努力变得复杂。这个项目的目标是开发出新的化学问题，以选择性调节插科打活性。我们将使用一个定向基于进化的方法来创建新的插科打aimetics - 多价糖肽附上短而活跃的HS基序 - 调节特定的HS-蛋白质相互作用。随机的通过定向进化对胡椒序列取样应允许选择结构包含HS主题的理想数量和排列。除了最佳HS聚类外，选定的宠物应包含感兴趣蛋白质识别的肽基序，因此产生高度特定的插科打问题。在AIM 1中，我们将与Krauss合作实验室开发方法并生成与选择性相互作用的HS模拟物成纤维细胞生长因子2（FGF2），这是细胞迁移，血管生成的关键生长因子，和分化。在AIM 2中，我们将进化与特定形式的tau，a结合的糖肽微管相关的蛋白质与痴呆症有关，例如阿尔茨海默氏病和帕金森氏病。我们将使用这些HS Mimetics了解基本机制 Tau摄取神经元和神经变性。此外，我们将探讨我们的模拟物可以阻止TAU的细胞间扩散及其致病后果。在AIM 3中，我们将进化结合趋化因子（特别是CXCL9，CXCL10和CXCL11）的糖肽，一类历史上重要的蛋白质是炎症的关键介质。我们的问题应该为趋化因子的悖论功能冗余提供独特的见解，使我们能够教授他们的个人角色。这些研究将共同产生小说基于插科打的类别的问题，以理解插科打的物理功能，并且可能最终导致新的治疗性铅或方法，例如癌症等疾病神经退行性疾病，炎症和自身免疫性疾病以及传染病。