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%的蛋白质产品是无法下药的，因为它们要么缺乏能够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。我的团队的一个目标是开发能够结合这些不可药物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。我们已经开发了一系列手性、环状构建块的合成，我们通过酰胺键对将这些构建块连接起来，以创建复杂的预先组织的螺旋梯形低聚物，称为双肽，重量在500至2000道尔顿之间。我们最近发现了一种新的化学方法，它允许我们在每一块积木上加入一个官能团。我们已经将这种化学发展到了可以创造高度功能化的大分子的地步，这些大分子可以以任何所需的三维排列来呈现蛋白生成和非蛋白生成基团。在“多样性导向合成”方面，这些低聚物凭借其受约束的性质和丰富的立体化学，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，它将模拟短？螺旋来结合螺旋结合蛋白；模拟长？螺旋来破坏螺旋卷曲；并在布鲁克海文蛋白质数据库中识别可以使用这些寡聚体来靶向的蛋白质-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，它与MDM2结合的亲和力比野生型P53肽更高，并被细胞摄取。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，并研究它们进入和阻止肝癌细胞生长的能力。 公共卫生相关性： “无法下药的蛋白质”是指估计有80%的人类蛋白质存在于细胞内，因此蛋白质疗法无法达到这些蛋白质，并且由于缺乏深疏水口袋而无法与小分子药物结合。我们正在开发一种通用的方法来合成500-2000道尔顿之间的形状可编程分子，这些分子能够像蛋白质一样显示出结合蛋白质表面的多种功能，同时仍然像小分子那样穿透细胞。这些分子将弥合小分子和蛋白质疗法之间的差距，并使我们能够针对目前被认为无法药物治疗的疾病相关蛋白质。

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.