Libraries of Template-Constrained Cyclic Peptides

这项研究的重点是开发一种组合方法，将给定的短肽序列锁定为各种不同的构象。然后将感兴趣的序列结合到包含用作构象调节元件的模板的大环中。模板分子的构象性质影响插入的四肽序列的构象，从而提供模板受限的环肽。潜在的靶肽将使用两个三肽序列，Arg-Gly-Asp(RGD)和Leu-Asp-Val(LDV)，它们是由细胞黏附整合素识别的。通过这一目标奖，多学科活动办公室和合成有机计划正在支持宾夕法尼亚大学生物化学和生物物理系的威廉·F·德格拉多博士和杜邦中央研究和发展部的马克·A·夏尔多博士的研究。该团队将专注于开发以各种构象状态呈现多肽的方法。这些方法应该用于设计和合成抑制各种多肽/蛋白质和蛋白质/蛋白质相互作用的多肽模拟物。这类化合物可能直接用作药品、诊断或农产品。

The focus of this research is to develop a combinatorial approach to lock a given short peptide sequence into a variety of different conformations. The sequence of interest is then incorporated into a macrocycle containing a template that serves as a conformational tuning element. The conformational properties of the template molecule influence the conformation of the intervening tetrapeptide sequence thus affording a template-constrained cyclic peptide. The potential target peptides will use two tripeptide sequences, Arg-Gly-Asp (RGD) and Leu-Asp-Val (LDV) which are recognized by the cell adhesion integrins. With this GOALI award, the Office of Multidisciplinary Activities and the Synthetic Organic Program are supporting the research of Dr. William F. DeGrado of the Department of Biochemistry and Biophysics at the University of Pennsylvania and Dr. Mark A. Scialdone of DuPont Central Research and Development. The team will focus on developing methodologies for the presentation of peptides in a variety of coformational states. These methods should have use for the design and synthesis of peptide mimetics that inhibit a variety of peptide/protein and protein/protein interactions. Such compounds might be useful directly as pharmaceuticals, diagnostics or agricultural products.