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Targeted degradation of proteins by affinity peptide conjugated ubiquitin (APCU)

通过亲和肽缀合泛素 (APCU) 靶向降解蛋白质

基本信息

批准号：
10391518
负责人：
FANGLIANG ZHANG
金额：
$ 16.36万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-12 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10391518
关键词：
Affect Affinity Aging Binding Biological Process C-terminal Cell Differentiation process Cell physiology Cells Chemicals DNA Disease Dose Engineering Enzymes Eukaryotic Cell Future Human Investigation Link Location MDM2 gene Malignant Neoplasms Mediating Methods Modeling Modification Molecular Probes Oncoproteins Pathway interactions Peptides Polyubiquitination Positioning Attribute Property Protac Protein Engineering Proteins RNA Reaction Reagent Regulation Research Design Resistance S-nitro-N-acetylpenicillamine Signaling Protein Specificity System Techniques Testing Therapeutic Therapeutic Effect Therapeutic Uses Ubiquitin Ubiquitination Viral Proteins affinity labeling analog base cancer type crosslink design experience feasibility testing in vivo misfolded protein myeloid leukemia cell novel novel strategies overexpression pathogen preclinical study protein degradation prototype response tool ubiquitin-protein ligase

项目摘要

Targeted degradation of proteins by affinity peptide conjugated ubiquitin (APCU) Protein degradation possesses many unique properties that cannot be covered by DNA/RNA manipulation tools. To understand the mechanism of biological processes, and to achieve desirable therapeutic effects, techniques designed to induce protein degradation are in critical needs. However, very few options are currently available for such purposes. Also, the existing tools have known limitations such as difficulty for adaptation or bell-shaped dose-response curve, or vulnerability for a negative regulation by the de- ubiquitination system. To expand the option for tools, and to overcome limitations of current methods, we propose to establish a new approach to induce protein degradation by conjugating a ubiquitin moiety with a molecule of high affinity to a target protein. For a proof or concept, peptides will first be used as the affinity molecule. This prototype is thus called affinity peptide conjugated ubiquitin (APCU). In our preliminary study, we designed a prototype APCU molecule with a peptide targeting MCL1, an oncoprotein that is over-expressed in many types of cancer. We found that this molecule can specifically reduce the level of MCL1 protein by promoting its degradation. In the proposed study, we will determine the action mechanism of the APCU approach and the optimal conditions for designing this types of molecules. We will also determine the dose response curve of the MCL1-targeting APCU and its sensitivity of de-ubiquitination system. Furthermore, to prepare for a wide usage and future in vivo applications, we will test the application of APCU on several other proteins and explore the feasibility of forming an APCU molecule with a conditional conjugation strategy. This proposed study, if secedes, will provide a highly valuable tool to specifically degrade a protein for mechanistic investigations and for potential therapeutic usages.

亲和肽偶联泛素（APCU）对蛋白质的靶向降解