Development of cell-permeable peptides and proteins

细胞渗透性肽和蛋白质的开发

• 批准号: 10405784
• 负责人: Dehua Pei
• 金额: $ 51.38万
• 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 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10405784
• 关键词: Affect; Area; Bacterial Toxins; Binding; Biological Products; Cell membrane; Cells; Chemicals; Cytosol; DNA Sequence Alteration; Development; Disease; Drug Delivery Systems; Drug Targeting; Endosomes; Enzymes; FDA approved; G-Protein-Coupled Receptors; Genetic Diseases; Goals; Human; Human Genetics; In Vitro; Investigation; Knowledge; Mammalian Cell; Membrane; Modality; Monoclonal Antibodies; Peptides; Periodicity; Permeability; Pharmaceutical Preparations; Pharmacological Treatment; Population; Property; Protein Secretion; Proteins; Research; Therapeutic; Tissue Engineering; extracellular; human disease; improved; in vivo; novel; novel drug class; protein protein interaction; small molecule; tool; tumor specificity; uptake

Project 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. In addition, there are ~7000 human genetic diseases affecting ~10% of the US population; only a very small fraction of them currently has pharmacologic treatment. The overall goal of my research is to develop a general approach to targeting the ~80% undruggable proteins and treating human genetic diseases. Accomplishing this goal requires effective delivery of large biomolecules into the mammalian cell. Over the past decade, my group has discovered a novel class of cyclic cell-penetrating peptides (CPPs), which efficiently deliver all major drug modalities into the cytosol of mammalian cells in vitro and in vivo, and elucidated their mechanism of endocytic uptake and endosomal escape. During the next five years, we will continue three areas of investigation. First, we will investigate how linear and cyclic CPPs directly translocate across the plasma membrane, how bacterial toxins and some human proteins escape the endosome into the cytosol, and how CPPs and some proteins exit the mammalian cell by a yet poorly defined “unconventional protein secretion” mechanism. Second, we will use the mechanistic knowledge gained to develop CPPs of improved properties, e.g., CPPs with specificity for tumor tissues, and engineer a mammalian membrane translocation domain (MTD) for intracellular delivery of proteins. Finally, we will leverage the cyclic CPPs and MTDs to develop cell-permeable peptides and proteins as chemical probes and potential therapeutics against several key “undruggable” targets.

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