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Disrupting Protein-Protein Interactions With Bis-peptides

用双肽破坏蛋白质-蛋白质相互作用

基本信息

批准号：
8214581
负责人：
Christian E Schafmeister
金额：
$ 29.75万
依托单位：
TEMPLE UNIV OF THE COMMONWEALTH
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-01-01 至 2014-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8214581
关键词：
Affinity Amides Amino Acids Antibodies Apoptosis Beds Binding Binding Proteins Biological Biological Assay Biology C-terminal Cell Culture Techniques Cell Proliferation Cells Charge Chemistry Circular Dichroism Collaborations Collection Complex Databases Development Dipeptides Disease Engineering Goals Growth Hepatitis B Virus Housing Human Human Genome In Vitro Lead Length Leucine Zippers Libraries Ligands Location Malignant Neoplasms Malignant neoplasm of liver Measurement Measures Methodology Modeling Molecular Nature Pair Bond Peptide Conformation Peptides Pharmaceutical Chemistry Pharmaceutical Preparations Protein Binding Proteins Reaction Relative (related person)Reporter Role Series Shapes Side Specific qualifier value Structure Surface Tertiary Protein Structure Testing Therapeutic Universities Vertebral column Virtual Library Weight Western Blotting c-myc Genes cancer cell dalton design diketopiperazine dimer functional group improved in vivo interest macromolecule mdm2 protein novel therapeutics pancreatic secretory trypsin inhibitor I professor protein protein interaction public health relevance small molecule software development stereochemistry therapeutic protein three dimensional structure tissue/cell culture tool

项目摘要

DESCRIPTION (provided by applicant): It has been estimated that 80% of the protein products of the human genome are "undruggable" because they either lack deep hydrophobic pockets that can bind small molecules or they are inside cells where antibodies and other biological drugs cannot reach them. A goal of my group is to develop molecules that can bind these undruggable proteins and penetrate cells to create new therapeutics and molecular tools to probe biology. We have developed a unique approach to the synthesis of chemically functionalized macromolecules with programmable shapes. We have developed the synthesis of a collection of chiral, cyclic building blocks that we connect through pairs of amide bonds to create complex and pre-organized spiro-ladder oligomers, called bis- peptides, between 500 and 2,000 Daltons in weight. We have recently discovered new chemistry that allows us to incorporate a functional group on every building block. We have developed this chemistry to the point where we can create highly functionalized macromolecules that can present proteogenic and non-proteogenic groups in any three- dimensional arrangement required. In terms of "diversity oriented synthesis" these oligomers have very diverse three-dimensional structures by virtue of their constrained nature and rich stereochemistry. We propose to use this synthetic methodology to create functionalized bis-peptides that will mimic short ?-helices to bind helix binding proteins; mimic long ?-helices to disrupt coiled-coils; and identify protein-protein interactions in the Brookhaven Protein Data Bank that can be targeted using these oligomers. In preliminary results we have demonstrated a functionalized bis-peptide that binds Mdm2 with higher affinity than the wild-type p53 peptide and is taken up by cells. We propose to develop functionalized bis-peptides that simultaneously bind Mdm2 and Mdmx and others that bind c-Myc and study their ability to enter and arrest growth in liver cancer cells. PUBLIC HEALTH RELEVANCE: "Undruggable proteins" are the estimated 80% of human proteins that are inside cells and thus unreachable by protein therapeutics and that cannot bind small molecule drugs because they lack a deep hydrophobic pocket. We are developing a general approach to synthesizing shape-programmable molecules between 500 - 2,000 Daltons that are able to display diverse functionality to bind protein surfaces as proteins do while still penetrating cells as small molecules do. These molecules will bridge the gap between small molecule and protein therapeutics and allow us to target disease related proteins that are currently considered undruggable.

描述（由申请人提供）：