Libraries of Template-Constrained Cyclic Peptides

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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.