Targeting protein-protein interactions using chemcial approaches

生命过程化学项目将通过这一奖项支持印第安纳大学医学院生物化学和分子生物学系的Hyun-Suk Lim教授开发新的蛋白质-蛋白质相互作用调节剂（PPIs）。这类PPI调节剂在化学生物学和药物化学领域的需求量很大。本文采用的方法包括设计、合成和评估构象受限的芳基桥接的环状/双环肽类化合物，这些肽类化合物带有仿螺旋片段。设计特点包括相对较大的尺寸，高结构多样性和增加的构象刚性，所有这些特征都有望促进与大而非连续的蛋白质界面的结合。与传统肽相比，这些环状肽类支架有望表现出更好的水溶性，优异的细胞渗透性和易于合成。该项目将使研究生和博士后接触到多学科的化学生物学环境，并具有显著的合成成分。该项目还将通过生命健康科学实习（LHSI）项目为印第安纳大学-普渡大学印第安纳波利斯分校（IUPUI）的本科生提供培训机会。此外，由IUPUI研究生办公室支持的少数族裔学生也将参与其中。林教授还将参与由IUPUI主导的“分布式药物发现”（D3）计划，将本科教育纳入寻找被忽视疾病的药物先导。

With this award, the Chemistry of Life Processes Program is supporting Professor Hyun-Suk Lim, of the Department of Biochemistry and Molecular Biology at Indiana University School of Medicine to develop new modulators of protein-protein interactions (PPIs). Such PPI modulators are in high demand in chemical biology and medicinal chemistry today. The approach taken here involves the design, synthesis and evaluation of conformationally constrained aryl-bridged cyclic/bicyclic peptoids bearing helix-mimetic segments. Design features include relatively large size, a high structural diversity, and increased conformational rigidity, all features expected to promote binding to large and non-contiguous protein interfaces Compared to conventional peptides, these cyclic peptoid scaffolds are expected to display improved aqueous solubility, excellent cell permeability and be easily accessed synthetically. This project will exposed graduate students and postdoctoral fellows to multidisciplinary chemical biology environment with a notable synthetic component. The project will also provide training opportunity to undergraduate students at Indiana University - Purdue University at Indianapolis (IUPUI) through the Life Health Science Internship (LHSI) program. In addition, underrepresented minority students supported by IUPUI Graduate Office will be involved. Professor Lim will also participate in "Distributed Drug Discovery" (D3) program led by IUPUI to incorporate undergraduate education into the search for drug leads for neglected diseases.