Disrupting Protein-Protein Interactions With Bis-peptides

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“不可药用的”，因为它们要么缺乏可以结合小分子的深疏水口袋，要么它们位于抗体和其他生物药物无法到达的细胞内。我的团队的一个目标是开发能够结合这些不可治疗的蛋白质并穿透细胞的分子，以创造新的治疗方法和分子工具来探测生物学。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。我们已经开发了一系列手性环状结构单元的合成，我们通过成对的酰胺键连接这些结构单元，以产生复杂的和预先组织的螺梯低聚物，称为双肽，重量在500和2,000道尔顿之间。我们最近发现了一种新的化学物质，可以让我们在每个构建单元上加入一个功能基团。我们已经将这种化学发展到可以产生高度官能化的大分子的程度，这些大分子可以以所需的任何三维排列呈现蛋白质生成和非蛋白质生成基团。在“多样性定向合成”方面，这些低聚物由于其受限性质和丰富的立体化学而具有非常多样的三维结构。我们建议使用这种合成方法来创建功能化的双肽，将模仿短？螺旋结合螺旋结合蛋白;模仿长？-螺旋以破坏卷曲螺旋;并鉴定Brookhaven蛋白质数据库中可以使用这些寡聚体靶向的蛋白质-蛋白质相互作用。在初步结果中，我们已经证明了一种功能化的双肽，其以比野生型p53肽更高的亲和力结合Mdm 2，并被细胞吸收。我们建议开发同时结合Mdm 2和Mdmx以及其他结合c-Myc的功能化双肽，并研究其进入肝癌细胞并抑制其生长的能力。

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.