EAGER: Dynamic helical inhibitors of protein-protein interfaces

生命过程化学项目向纽约大学化学系的内维尔·R·卡伦巴赫教授提供了这笔热切的资助。蛋白质是生物体中最重要的活性物质，对细胞和组织的形状、结构和功能起着重要的作用。蛋白质分子的一个关键作用是识别和特定地与其他蛋白质相互作用。控制蛋白质分子之间这些相互作用的能力提供了一种干预几乎任何重要过程的手段，包括细胞生长、发育、信号和转化。许多目前重要的药物是干扰蛋白质表面的小分子，这些小分子与其他蛋白质接触。现代药物开发面临的一个关键问题是，我们无法控制大量的蛋白质相互作用表面，这些表面没有提供使小分子干预成为可能的有利特征(如结合口袋)。该项目开发了一种对广泛的无特征的、延伸的螺旋蛋白质-蛋白质界面施加化学控制的一般策略。该方法旨在生产具有生物活性的多肽和蛋白质片段，而不是传统的小分子。首先，该团队将精心制作可以通过夹子进行结构锁定的短肽，以增强其稳定性和结合亲和力。下一步，他们将合成具有数千种不同序列的10-12个氨基酸多肽的随机“文库”，每个序列都包含反应性夹子。最后，他们将利用多肽对特定目标蛋白的选择性“粘性”来促进仅对最紧密结合的化合物的夹持。这种策略不是通过冻结精确定位的连接子来选择单个靶点，而是能够对一系列特殊的扩展的、以前无法下药的接口进行全球攻击，这些接口无法通过小分子抑制来接近。虽然完整的蛋白质，生物制品，也可以选择性地抑制蛋白质-蛋白质界面，但这些都是昂贵的、不稳定的和不可生物利用的。这项研究的产品将比生物制品更稳定、更经济，而且比小分子更通用、更有选择性，更不可能遇到突变抗性。该项目的最初目标是蛋白质-蛋白质界面，它对微管的形成至关重要，微管是细胞分裂的关键结构。阻止微管组装的小分子包括重要的抗肿瘤药物。一个成功的结果将确定一条新的途径来发现一系列目前无法下药的蛋白质界面的抑制剂，一类新的试剂和疗法，相对于现有的小分子替代品具有特殊的选择性和亲和力。这个项目将允许研究人员培训现代化学生物学方面的本科生、研究生和博士后研究员，这是一种宝贵的教育经验。此外，该项目的成果将在各种会议上传播，并通过期刊出版物传播。Kallenbach为一组学院和大学(包括10所HBCU和波多黎各大学的11个校区)的教师组织和指导促进教师发展的科学讲习班。未来将提供一个化学生物学研讨会，以现代药理学中的高通量方法为中心，这项研究的产品将展示给来自不同机构的科学教师。

The Chemistry of Life Processes program supports this EAGER grant to Professor Neville R. Kallenbach of the Department of Chemistry, New York University. Proteins are the most vital active agents in living matter, responsible for the shape, structure and function of cells and tissues. One key role of protein molecules is to recognize and interact specifically with other proteins. The ability to control these interactions among protein molecules affords a means of intervening in almost any vital process, including cell growth, development, signaling and transformation. Many currently important drugs are small molecules that interfere with the surfaces of proteins that make contacts with other proteins. A critical problem facing modern drug development centers on our inability to control the large number of protein-protein interacting surfaces that do not present favorable features (such as binding pockets) that make small molecule intervention possible. This project develops a general strategy to exert chemical control over a wide range of featureless, extended helical protein-protein interfaces. The approach is designed to produce biologically active peptides, fragments of proteins, rather than traditional small molecules. First, the team will elaborate short peptides that can be structurally locked-in by clamps to enhance their stability and binding affinity. Next, they will synthesize random "libraries" of 10- 12 amino acid peptides with thousands of different sequences, each containing the reactive clamps. Finally, they will use the selective "stickiness" of the peptides to specific target proteins to promote clamping of only the tightest binding compounds. Instead of selecting individual targets by freezing-in precisely positioned linkers, this strategy enables a global attack on an exceptional range of extended and previously "undruggable" interfaces that cannot be approached by small molecule inhibition. While intact proteins, biologics, can also selectively inhibit protein-protein interfaces, these are expensive, unstable and not bioavailable. The products of this research will be more stable and economical to produce than biologics, as well as more versatile, selective and less likely to encounter mutational resistance than small molecules. The initial target of the project is the protein-protein interface that is crucial for formation of microtubules, structures essential for cell division. Small molecules that block microtubule assembly include important antitumor agents. A successful outcome would identify a new route to discover inhibitors of a wide range of currently "undruggable" protein interfaces, a class of new reagents and therapeutics with exceptional selectivity and affinity relative to existing small molecule alternatives.This project will allow the investigator to train undergraduates, a graduate student, and a postdoctoral fellow in modern chemical biology, a valuable educational experience. In addition the results of the project will be disseminated at conferences and meetings and by means of journal publications. Kallenbach has organized and directed science workshops for faculty from a group of colleges and universities (including 10 HBCUs and 11 campuses of the University of Puerto Rico) that promote faculty development. A future chemical biology workshop will be offered that centers on high throughput approaches in modern pharmacology, and the products of this research will be presented to science faculty from a diverse set of institutions.