CDS&E: Cyclic Tetrapeptide Probes For Protein Binding

通过这个奖项，化学部门的生命过程化学项目资助了德克萨斯农工大学的凯文·伯吉斯博士，以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，小分子可以帮助或阻碍蛋白质之间的相互作用，这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相互作用的影响。它还为研究生和本科生提供化学合成、计算机辅助分子设计和数据挖掘培训，帮助他们解决当代生命科学中的问题。已知环肽可以模拟蛋白质-蛋白质相互作用的关键区域，即蛋白质-蛋白质界面（PPI）模拟物。虽然环状五肽很容易制造，但它们倾向于在构象之间保持平衡。相反，天然氨基酸中的环四肽很难合成，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等大小的环，即3n个原子（n = #氨基酸），而忽略了结合构象刚性和易于合成的12和15之间的环大小。这项工作表明，与一些早期的报道相反，天然氨基酸的环四肽具有构象刚性，并且比以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用来获得环四肽，这些环四肽位于易于合成和构象刚性之间的有用十字路口。

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.