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.

项目概要糖胺聚糖（GAG）在许多生理和病理事件中发挥重要作用例如细胞分裂、炎症、神经发育和癌症转移。 GAG 的多糖链含有各种硫酸化二糖，这些二糖被组织成这种丰富的结构多样性使得 GAG 能够形成诸如硫酸乙酰肝素 (HS) 与多种蛋白质相互作用并调节关键信号通路。然而，努力理解它们的结构-功能关系并利用它们由于 GAG 的化学复杂性和缺乏目前，还没有工具可以操纵 GAG 与特定蛋白质的相互作用。兴趣，从而使确定其确切角色的工作变得复杂。该项目的目标是开发用于选择性调节 GAG 活性的新型化学探针。基于进化的方法创建一类新的 GAG 模拟物——多价糖肽附加短的、活跃的 HS 基序——调节特定的 HS-蛋白质随机相互作用。通过定向进化对肽序列进行采样应允许选择结构除了最佳的 HS 聚类之外，还包含理想的 HS 基序数量和排列。选定的肽应包含感兴趣的蛋白质识别的肽基序，因此在目标 1 中，我们将与 Krauss 合作生成高度特异性的 GAG 探针。实验室开发该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)，一种参与细胞迁移、血管生成、在目标 2 中，我们将进化出与特定形式的 tau 蛋白结合的糖肽。微管相关蛋白与阿尔茨海默病等痴呆症有关我们将使用这些 HS 模拟物来了解其潜在机制。此外，我们还将探讨我们的神经元摄取 tau 蛋白是否会导致神经变性。在目标 3 中，模拟物可以阻断 tau 蛋白的细胞间扩散及其致病后果。我们将进化出结合趋化因子的糖肽（特别是CXCL9、CXCL10和CXCL11），一类具有重要治疗意义的蛋白质，是炎症的关键介质。应该对趋化因子的矛盾功能冗余提供独特的见解，这些研究使我们能够梳理出他们各自的角色，从而创作出一部小说。一类基于 GAG 的探针，用于了解 GAG 的生理功能，并且可能最终导致癌症等疾病的新治疗线索或方法，神经退行性疾病、炎症和自身免疫性疾病以及传染病。