Development of Cell-Permeable Peptides and Proteins

细胞渗透性肽和蛋白质的开发

• 批准号: 9273789
• 负责人: Dehua Pei
• 金额: $ 40.14万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9273789
• 关键词: Binding; Calcineurin; Cells; Cyclic Peptides; Development; Diffuse; Disease; Drug Targeting; Enzymes; FDA approved; Five-Year Plans; Goals; Human; Inflammation; Knowledge; Laboratories; Libraries; Malignant Neoplasms; Mammalian Cell; Metabolic; Methodology; Molecular Weight; Mono-S; Monoclonal Antibodies; Peptides; Periodicity; Permeability; Pharmaceutical Preparations; Property; Proteins; Research; Therapeutic Human Experimentation; Tumor Tissue; Work; design; extracellular; human disease; improved; inhibitor/antagonist; novel; protein protein interaction; screening; small molecule; tool; tumor specificity

Research Summary Current FDA-approved drugs are usually either small molecules (MW <500) or large proteins (MW >5000). Small molecules are generally limited to targeting proteins and other biomolecules that contain deep binding pockets (e.g., enzymes and GPCRs), which represent ~10% of all disease relevant human proteins. On the other hand, biologics (e.g., monoclonal antibodies) are restricted to extracellular targets, which represent another ~10% of all drug targets. The remaining ~80% drug targets, which are primarily proteins involved in intracellular protein-protein interactions (PPIs), are currently undruggable by either approach. The same limitations apply to the use of small molecules and proteins as research tools. The overall goal of my research is to develop a general approach to targeting the ~80% undruggable proteins. Recent work from my lab as well as many other laboratories has demonstrated that mono- and bicyclic peptides in the 700-2000 molecular-weight range act as effective PPI inhibitors. My group further demonstrated that by integrating a newly discovered class of cyclic cell-penetrating peptides (CPPs) into our compound design, we can generate cell-permeable and metabolically stable cyclic peptide inhibitors against a wide variety of intracellular enzymes and PPIs. During the next five years, we plan to further investigate the mechanism of action of these cyclic CPPs and use the knowledge to develop additional CPPs of improved properties, e.g., CPPs with specificity for tumor tissues. The CPPs will be explored for delivery of proteins as therapeutics and research tools. Efforts will also be made to optimize the potency, selectivity, metabolic stability, and other drug properties of cyclic peptide inhibitors already discovered against several important drug targets including calcineurin, CAL PDZ domain, and NEMO. Finally, we plan to develop a novel methodology for synthesizing and screening large libraries of non-peptidyl macrocycles that can passively diffuse into mammalian cells and act as inhibitors against intracellular proteins such as PPIs.

研究总结 目前FDA批准的药物通常是小分子(MW&lt；500)或大蛋白质(MW&lt；500) &gt；5000)。小分子通常仅限于靶向蛋白质和其他含有 深层结合口袋(例如，酶和GPCR)，占所有与疾病相关的人类的10% 蛋白质。另一方面，生物制品(例如，单抗)仅限于细胞外靶点， 占所有药物靶点的另外10%。剩下的~80%的药物靶点，主要是 参与细胞内蛋白质-蛋白质相互作用(PPI)的蛋白质目前都不能被任何一种药物所抑制 接近。同样的限制也适用于使用小分子和蛋白质作为研究工具。这个 我研究的总体目标是开发一种通用的方法来瞄准~80%无法用药的人 蛋白质。我的实验室以及许多其他实验室最近的研究表明，单核细胞和 分子量在700-2000范围内的双环肽是有效的PPI抑制剂。我的小组更进一步 证明了通过将一类新发现的环状细胞穿透肽(CPP)整合到 我们的化合物设计，我们可以产生细胞渗透性和代谢稳定的环肽抑制剂 对抗多种胞内酶和PPI。在未来五年，我们计划进一步 研究这些循环CPP的作用机制，并利用这些知识开发出更多 性质得到改善的CPPs，例如对肿瘤组织具有特异性的CPPs。将探讨国家方案规划，以 将蛋白质作为治疗和研究工具。还将努力优化效力， 已发现的环肽抑制剂的选择性、代谢稳定性和其他药物特性 针对几个重要的药物靶点，包括钙调神经磷酸酶、CAL PDZ结构域和NEMO。最后，我们 计划开发一种新的方法来合成和筛选大型非肽文库 可以被动地扩散到哺乳动物细胞中并作为细胞内抑制物的大周期 蛋白质，如PPI。