CAREER: Combinatorial Chemistry in the Classroom and Laboratory: Identification of Novel Small Molecule Ligands for Apoptotic Proteins

在化学系有机动力学项目的支持下，伊利诺伊大学厄巴纳-香槟分校化学系的Paul Hergenrother教授将研究使用小分子来研究和调节生物系统。该研究的总体目标是合成，鉴定和使用与细胞凋亡相关的蛋白质紧密和选择性结合的小分子。提出了一种细胞凋亡的方法，其中合成与其蛋白质靶紧密结合的小分子，然后在体内用于“敲除”途径中的蛋白质。这些分子将是研究这个极其重要的系统的宝贵工具，它们也有可能作为治疗剂。最初的蛋白质靶点将是半胱氨酸蛋白酶的半胱天冬酶家族，以及细胞凋亡的调节因子如Smac/DLABLO和IAP。用于本研究的小分子将以组合方式在固相上合成，然后筛选作为小分子微阵列的结合。小分子微阵列的使用是必不可少的，因为它将允许针对多个蛋白质靶标快速评估文库，并评估合成化合物对一种半胱天冬酶相对于另一种半胱天冬酶的选择性。针对半胱天冬酶的文库将是“集中的”文库，并且将在结构上偏向于将抑制半胱氨酸蛋白酶的化合物。将针对Smac/DIABLO、IAP和其他凋亡蛋白筛选的文库是“初级”文库，其中已尝试使文库内的多样性最大化。这种包含多种化学支架的初级文库尚未在固相上产生，并且本文所述文库的成功产生将代表组合合成的重大进步。伊利诺伊大学厄巴纳-香槟分校化学系的Paul Hergenrother教授在有机动力学计划的支持下获得了他的职业奖，还将开发一个综合方案，用于在课堂上教授组合化学，并在实验室中应用组合化学和高通量筛选。学生培训的最终目标是创建一个研究处于化学-生物学界面前沿的小组，同时培养学生从细胞和分子生物学到有机合成的各种技能。

With the support of the Organic Dynamics Program in the Chemistry Division, Professor Paul Hergenrother, of the Department of Chemistry at the University of Illinois- Urbana-Champaign, will investigate using small molecules to investigate and modulate biological systems. The overall goal of the research being the synthesis, identification, and use of small molecules that bind tightly and selectively to proteins involved in apoptosis. An approach to apoptosis is proposed in which small molecules that bind tightly to their protein target are synthesized and then used in vivo to "knock-out" the proteins in the pathway. Such molecules will be invaluable tools in the study of this exquisitely important system, and they also have potential as therapeutic agents. Initial protein targets will be the caspase family of cysteine proteases, as well as regulators of apoptosis such as Smac/DLABLO and IAP. The small molecules used for this study will be synthesized on the solid phase in a combinatorial fashion, and then screened for binding as small molecule microarrays. Use of small molecule microarrays are essential, as it will allow for both rapid evaluation of the library against multiple protein targets, and assessment of the selectivity of the synthesized compounds for one caspase versus another. The library aimed at the caspases will be a "focused" library and will be structurally biased towards compounds that will inhibit cysteine proteases. The library that will be screened against Smac/DIABLO, IAP, and other apoptotic proteins is a "primary" library in which an attempt has been made to maximize the diversity within the library. Such primary libraries that incorporate multiple chemical scaffolds have not been created on the solid phase, and the successful production of the library described herein will represent a significant advance in combinatorial synthesis.Professor Paul Hergenrother, of the Department of Chemistry at the University of Illinois- Urbana-Champaign, with the support of the Organic Dynamics Program for his CAREER award, will also develop an integrated program for teaching combinatorial chemistry in the classroom and applying combinatorial chemistry and high-throughput screening in the laboratory. The ultimate goal in the training of students is to create a group whose research is on the cutting edge of the chemistry-biology interface while developing in the student a wide variety of skills, from cell and molecular biology to organic synthesis.