Ubiquitin-independent targeted protein degradation

不依赖泛素的靶向蛋白质降解

基本信息

批准号：
10678852
负责人：
Lizbeth K. Hedstrom
金额：
$ 69.16万
依托单位：
BRANDEIS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10678852
关键词：
26S proteasome Active Sites Address Binding Cells Chimera organism Complex Cyclization DNA Diabetes Mellitus Disease Dose Drug Design Event Goals Grant In Vitro Inflammation Laboratories Libraries Ligand Binding Ligands Ligase Link Malignant Neoplasms Messenger RNA Methods Nature Peptide Hydrolases Peptides Permeability Pharmaceutical Preparations Positioning Attribute Post-Translational Protein Processing Proteasome Binding Proteins Role Route Site-Directed Mutagenesis Tissues UBA Domain UBQLN1 gene Ubiquitin Ubiquitination Work antagonist cancer therapy design drug discovery experimental study improved inhibitor innovation insight multicatalytic endopeptidase complex particle peptidomimetics protein degradation prototype rational design receptor response small molecule tissue/cell culture ubiquitin-protein ligase unfoldase unnatural amino acids

项目摘要

Project Summary Targeted protein degradation is an exciting new strategy in drug discovery. Such drugs have several potential advantages: (1) new protein targets must be synthesized to reverse the effect of the drug, potentially prolonging efficacy; (2) all the domains of the target protein are inactivated, potentially eliciting different responses than inhibition of a single active site; (3) each drug molecule can inactivate multiple target molecules, making efficacy event-driven rather than occupancy-driven, potentially lowering dose and (4) simple binders can be converted into functional compounds, which may address targets considered “undruggable”. The rational design of drugs inducing target degradation has almost exclusively focused on a single over-arching strategy: localization of the target protein to a ubiquitin E3 ligase. The primary role of ubiquitination is to localize the target protein to the proteasome, and experiments from several laboratories demonstrate that proteasome localization is sufficient to induce degradation. These observations suggest a ubiquitin-independent strategy for targeted protein degradation, wherein a target recognition ligand is linked to a proteasome binding ligand (proteasome recruiter). Direct localization to the proteasome avoids issues with E3 ligase localization strategies. Proteasome recruiters also have the potential to be tissue, compartment and cancer-specific. The goal of this transformative grant is to demonstrate the feasibility of proteasome recruiters using three strategies: (1) Localization to the 19S regulatory particle; (2) Localization to a proteasome shuttle factor and (3) localization to the alpha ring of the 20S proteasome.

项目概要靶向蛋白质降解是此类药物发现中令人兴奋的新策略。几个潜在的优势：（1）必须合成新的蛋白质靶标才能逆转效应药物的，可能延长疗效；（2）靶蛋白的所有结构域都是失活，可能引发与抑制单个活性位点不同的反应；每个药物分子可以灭活多个靶分子，使疗效由事件驱动而不是占用驱动，可以潜在地降低剂量和（4）简单的粘合剂转化为功能性化合物，可以解决被认为“无法成药”的目标。诱导靶点降解药物的合理设计几乎完全集中在单一总体策略：将靶蛋白定位于泛素 E3 连接酶。泛素化的主要作用是将靶蛋白定位于蛋白酶体，实验多个实验室证明蛋白酶体定位足以诱导这些观察结果表明，针对目标蛋白存在一种不依赖于泛素的策略。降解，导致目标识别配体与蛋白酶体结合配体连接（蛋白酶体招募员）。直接定位到蛋白酶体可避免 E3 连接酶的问题。蛋白酶体招募者也有可能是组织、区室。这项变革性拨款的目标是证明其可行性。蛋白酶体招募者使用三种策略：（1）定位到 19S 调节颗粒；（2）蛋白酶体穿梭因子的定位和 (3) 20S α 环的定位蛋白酶体。