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Molecular Cloaking Devices for Manipulation of Cysteine Post-Translational Modifications

用于操纵半胱氨酸翻译后修饰的分子隐藏装置

基本信息

批准号：
10507541
负责人：
Thomas J. Kodadek
金额：
$ 49.68万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-19 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10507541
关键词：
Active Sites Affect Affinity Agonist Alkylation Area Binding Biology C-terminal Cell membrane Cells Chemotherapy-Oncologic Procedure Cyclic Peptides Cysteine DNA Development Devices Enzymes Epitopes Event Family member Generations Goals Intervention KRAS2 gene Lead Libraries Ligands Mediating Methods Modification Molecular Oncogenic Operative Surgical Procedures Pathway interactions Peptides Permeability Pharmaceutical Preparations Pharmacology Post-Translational Modification Site Post-Translational Protein Processing Proteins Publishing RAS genes Reaction Regulation Signal Pathway Signaling Protein Site Source Sulfhydryl Compounds Technology Time Work base clinical development combinatorial drug development enzyme substrate extracellular inhibitor mutant novel prenylation prevent protein function uncontrolled cell growth virtual

项目摘要

Project Summary Post-translational modifications (PTMs) of proteins are involved in virtually all cellular signaling pathways. Pharmacological intervention in these events is an important strategy for drug development. In this project, we propose to establish a novel platform for the discovery of covalent inhibitors of cysteine post-translational modifications, in particular, the prenylation of the C-termini of H-Ras and K-Ras. These events are critical for oncogenic mutants of these proteins to drive cell uncontrolled growth and division. In contrast to typical strategies for blocking PTMs, we will screen for non-peptidic macrocycles that bind covalently to the modified epitope on the substrate protein (H-Ras or K-Ras), rather than compounds that target the modifying enzyme. In this way, we believe it will be possible to manipulate single PTMs with unprecedented selectivity.

项目摘要蛋白质的翻译后修饰(PTM)几乎参与了所有的细胞信号通路。对这些事件的药物干预是药物开发的重要策略。在这个项目中，我们建议建立一个发现半胱氨酸翻译后共价抑制剂的新平台修饰，特别是H-RAS和K-RAS的C-末端的戊烯基化。这些事件对于这些蛋白质的致癌突变以驱动细胞不受控制的生长和分裂。与典型的阻断PTMS的策略，我们将筛选与修饰的大环共价结合的非肽大环底物蛋白(H-RAS或K-RAS)上的表位，而不是以修饰酶为靶点的化合物。在……里面这样，我们相信将有可能以前所未有的选择性操纵单个PTM。