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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：
8606215
负责人：
Christian E Schafmeister
金额：
$ 30.6万
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 2015-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8606215
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 Geometry 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.

描述（由申请人提供）：据估计，人类基因组中80%的蛋白质产物是“不可成药的”，因为它们要么缺乏可以结合小分子的深层疏水口袋，要么位于抗体和其他生物药物无法到达的细胞内部。我的团队的目标是开发能够结合这些不可成药的蛋白质并穿透细胞的分子，以创造新的疗法和分子工具来探索生物学。我们开发了一种独特的方法来合成具有可编程形状的化学功能化大分子。我们开发了一系列手性环状结构单元的合成方法，我们通过成对的酰胺键连接这些结构单元，以创建复杂且预先组织的螺梯低聚物，称为双肽，重量在 500 至 2,000 道尔顿之间。我们最近发现了新的化学物质，使我们能够在每个构建块上结合一个官能团。我们已经将这种化学发展到了可以创造出高度功能化的大分子的程度，这些大分子可以以任何所需的三维排列呈现蛋白质和非蛋白质基团。就“多样性导向合成”而言，这些低聚物由于其受限的性质和丰富的立体化学而具有非常多样化的三维结构。我们建议使用这种合成方法来创建功能化的双肽，该双肽将模拟短的β-螺旋以结合螺旋结合蛋白；模仿长 β-螺旋来破坏卷曲线圈；并确定布鲁克海文蛋白质数据库中可以使用这些寡聚物靶向的蛋白质-蛋白质相互作用。在初步结果中，我们证明了一种功能化双肽，它比野生型 p53 肽以更高的亲和力结合 Mdm2，并被细胞吸收。我们建议开发同时结合 Mdm2 和 Mdmx 以及其他结合 c-Myc 的功能化双肽，并研究它们进入肝癌细胞并阻止其生长的能力。