Development of Cell-Permeable Peptides and Proteins

细胞渗透性肽和蛋白质的开发

• 批准号: 9925805
• 负责人: Dehua Pei
• 金额: $ 49.95万
• 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/9925805
• 关键词: Binding; Biological; Calcineurin; Cells; Cyclic Peptides; Development; Diffuse; Disease; Drug Targeting; Enzymes; FDA approved; Five-Year Plans; G-Protein-Coupled Receptors; Goals; Human; Inflammation; Knowledge; Laboratories; Libraries; Malignant Neoplasms; Mammalian Cell; Metabolic; Methodology; Molecular Weight; 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.

研究摘要 当前FDA批准的药物通常是小分子（MW <500）或大蛋白（MW > 5000）。小分子通常仅限于靶向蛋白质和其他包含的生物分子 深层结合口袋（例如酶和GPCR），占所有相关人的约10％ 蛋白质。另一方面，生物制剂（例如，单克隆抗体）仅限于细胞外靶标， 占所有药物靶标的约10％。其余约80％的药物靶标主要是 目前，任何一种参与细胞内蛋白质蛋白质相互作用（PPI）的蛋白质目前不可用 方法。使用小分子和蛋白质作为研究工具也有相同的限制。这 我的研究的总体目标是开发一种针对约80％不利的总体方法 蛋白质。我的实验室以及许多其他实验室的最新工作表明，单声道和 700-2000分子量范围内的双环肽可作为有效的PPI抑制剂。我的小组进一步 证明，通过整合新发现的一类环状细胞 - 渗透肽（CPP） 我们的复合设计，我们可以生成可渗透和代谢稳定的环状肽抑制剂 针对各种细胞内酶和PPI。在接下来的五年中，我们计划进一步 研究这些环状CPP的作用机理，并利用知识来开发更多 改善特性的CPP，例如具有特异性的CPP对肿瘤组织。 CPP将被探索 蛋白质作为治疗和研究工具的递送。还将努力优化效力， 已经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标，包括钙调神经酶，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非肽基的大型文库 可以被动扩散到哺乳动物细胞并起到细胞内的抑制剂的大环细胞 蛋白质，例如PPI。