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Chemical Probes of Protein Tyrosine Phosphatase Activity

蛋白质酪氨酸磷酸酶活性的化学探针

基本信息

批准号：
10462592
负责人：
AMY M BARRIOS
金额：
$ 28.98万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-20 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10462592
关键词：
Address Alkanesulfonates Autoimmunity Biochemistry Biological Biological Assay Biological Availability Biology Cardiovascular Diseases Cells Charge Chemicals Communities Complex Data Development Diabetes Mellitus Disease Drug Targeting Enzymatic Biochemistry Enzymes Event Expeditions Failure Family Fluorescence Fluorogenic Substrate Human Genome In Vitro Individual Interdisciplinary Study Investigation Laboratories Ligands Light Literature Malignant Neoplasms Metabolic Diseases Molecular Molecular Weight Monitor Oncogenic PTPN1 gene PTPN11 gene PTPRC gene Peptides Permeability Pharmaceutical Preparations Phosphoric Monoester Hydrolases Phosphorylation Phosphotyrosine Play Process Protein Dephosphorylation Protein Tyrosine Kinase Protein Tyrosine Phosphatase Regulation Reporter Reporting Research Role Series Signal Pathway Signal Transduction Synthesis Chemistry Techniques Technology Tyrosine Tyrosine Phosphorylation Validation Work base chemical synthesis comparative design drug discovery extracellular high throughput screening human disease in vitro activity inhibitor innovation interest member mimetics new therapeutic target novel phosphatase inhibitor programs protein aminoacid sequence receptor scaffold screening small molecule success therapeutic target tissue culture tool

项目摘要

Project Summary Tyrosine phosphorylation is a key regulatory event in multiple cellular signaling pathways. The phosphorylation and dephosphorylation of tyrosine, catalyzed by protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs), respectively, is a tightly regulated process. Despite the approximately equal numbers of PTKs and PTPs in the human genome and similar degrees of substrate selectivity and parallel biological regulation, comparatively little is known about PTP activity in contrast to the significant body of literature dealing with the roles of PTKs in cellular signaling. In particular, activity-based chemical probes that directly report on PTP activity are of great interest because they would provide the means to monitor PTP activity in living cells and also facilitate the study of individual PTPs in complex signaling pathways. The long-term objective of our work is to develop chemical approaches to studying PTP activity that can be used to answer key questions about PTP biology. Recently, we have developed a PTP- platform technology that facilitates monitoring the activity of individual PTPs both in vitro and in cells. This technology involves delivering fluorogenic peptide substrates to cells and monitoring changes in fluorescence of the cells as intracellular PTPs act on the substrate. Based on our previous success with selectively monitoring PTP activity in cells using peptide substrates, we now develop targeted probes for several members of the PTP family of enzymes. Specifically, we will develop a series of selective substrates and inhibitors for PTP activity that can be used to monitor the cellular activity of multiple PTPs and address key questions about PTP biology. Our approach can readily be applied to almost any member of the PTP family of enzymes and we have selected a representative group for our initial investigation. In addition, our approach should prove very useful in the development of generic PTP-targeted, mechanism-based probes as well. The multidisciplinary research program described here takes advantage of the Barrios laboratory’s expertise in chemical synthesis, biochemistry and enzymology and will provide probes of great interest to the signaling biology research community.

项目摘要酪氨酸磷酸化是多种细胞信号传导途径中的关键调节事件。的蛋白酪氨酸激酶催化的酪氨酸磷酸化和去磷酸化蛋白酪氨酸磷酸酶（PTK）和蛋白酪氨酸磷酸酶（PTPs）分别是一个严格调控的过程。尽管人类基因组中PTK和PTPs的数量大致相等，程度的底物选择性和平行的生物调节，相对知之甚少与大量涉及PTK作用的文献相比，关于PTP活动在细胞信号中。特别是，直接报告PTP的基于活性的化学探针活动是非常感兴趣的，因为它们将提供监测PTP活动的手段，活细胞，也促进了复杂信号通路中单个PTP的研究。的我们工作的长期目标是开发研究PTP活性的化学方法，可以用来回答PTP生物学的关键问题。最近，我们开发了一种PTP- 该平台技术有助于在体外和体内监测单个PTP的活性，细胞该技术涉及将荧光肽底物递送至细胞并监测当细胞内PTP作用于底物时，细胞的荧光发生变化。基于我们以前的成功与选择性监测PTP活性在细胞中使用肽底物，我们现在开发针对PTP酶家族的几个成员的靶向探针。具体地说，我们将开发一系列PTP活性的选择性底物和抑制剂，用于监测多种PTP的细胞活性，并解决以下关键问题： PTP生物学。我们的方法可以很容易地应用于几乎任何成员的PTP家庭，我们选择了一个有代表性的组进行初步研究。此外，本发明还提供了一种方法，我们的方法应该证明在开发通用PTP靶向，也是基于机制的探测器。这里描述的多学科研究计划需要利用巴里奥斯实验室在化学合成、生物化学和生物技术方面的专业知识，将为信号生物学研究提供具有重要意义的探针社区