CDS&E: Cyclic Tetrapeptide Probes For Protein Binding

通过这一奖项，化学系的生命过程化学项目将资助德克萨斯农工大学的Kevin Burgess博士发现影响某些蛋白质相互结合的小分子。蛋白质之间的相互作用对细胞中的许多生物过程都很重要。因此，拥有可以帮助或阻碍蛋白质相互作用的小分子可能会导致潜在的新药来帮助治疗各种疾病。该项目正在创造新的小分子，并研究它们对蛋白质-蛋白质相互作用的影响。它还结合了化学合成、计算机辅助分子设计和面向研究生和本科生的数据挖掘培训，帮助他们解决当代生命科学中的问题。环肽可以模拟蛋白质间相互作用的关键区域，即模拟蛋白质-蛋白质界面(PPI)。虽然环状五肽很容易制造，但它们往往会在构象之间达到平衡。相反，来自天然氨基酸的环状四肽很难制备，但构象更稳定。因此，由主链酰胺连接的遗传编码氨基酸容易合成的环肽可以具有9、12、15等环大小，即3n个原子(n=#个氨基酸)，这错过了12到15之间的环大小，这结合了构象刚性和易于合成。这项工作表明，与一些早期的报告相反，来自天然氨基酸的环状四肽是构象刚性的，比之前认为的更容易合成。它还表明，用一些刚性的非天然氨基酸取代遗传编码的残基可以得到处于合成简便性和构象刚性之间的有用的十字路口的环状四肽。

With this award, the Chemistry of Life Processes Program in the Chemistry Division is funding Dr. Kevin Burgess of Texas A & M University to discover small molecules that affect how some proteins bind to each other. Protein-protein interactions are important to many biological processes in cells. Thus having small molecules that can either aid or or hinder protein-protein interactions could lead to potential new drugs to help treat various diseases. The project is creating new small molecules and studying their effect on protein-protein interactions. It also combines chemical synthesis, computer-aided molecular design and data-mining training for graduate and undergraduate students to help them tackle problems in contemporary life science. Cyclic peptides are known to mimic key regions involved in protein-protein interactions, i.e. to be Protein-Protein Interface (PPI) mimics. While cyclic pentapeptides are easy to make they tend to equilibrate between conformers. Conversely cyclic tetrapeptides from natural amino acids are difficult to make but are more conformationally stable. Thus, easily synthesized cyclic peptides from genetically encoded amino acids linked by main-chain amides can have ring sizes of 9, 12, 15, etc. i.e. 3n atoms, (n = # amino acids) which misses ring sizes between 12 and 15 that combine conformational rigidity with ease of synthesis. This work is showing that contrary to some earlier reports, cyclic Tetrapeptides from natural amino acids are conformationally rigid and are more synthetically accessible than previously thought. It is also showing that replacement of a genetically encoded residue with some rigid unnatural amino acids can be used to give cyclic tetrapeptides that rest at a useful crossroads between ease of synthesis and conformational rigidity.