University of Pittsburgh
Protein Tertiary Structure Mimetics through Systematic Alteration of Backbone Covalent Connectivity
The structural diversity of proteins in nature is vast and the foundation for their unparalleled functional versatility. Inspired by nature’s example, chemists have long sought to create synthetic molecular entities that fold in defined ways. Termed "foldamers," such agents have found applications in areas from biomedical to materials science.
Progress in foldamer design and synthesis in recent years have led to bioinspired as well as abiotic secondary structures, high-affinity ligands for biomacromolecular surfaces, and complex multi-molecular assemblies. These impressive advances notwithstanding, the structural diversity shown possible to date still pales in comparison to the array of folding motifs found in nature.
This talk will describe recent work toward a general strategy for creating foldamer mimics of protein tertiary structures through the systematic alteration of backbone covalent connectivity in natural sequences. Our approach is based on the idea that any protein can be thought of as having two sequences: one of amino acid side chains and another of backbone units that display those side chains.
In work to date, we have leveraged this concept to create “heterogeneous-backbone” mimics of a range of prototype sequences with complex folded architectures. Collectively, results from these ongoing efforts expand the scope of structures and functions possible in foldamers and suggest new ways to control properties such as folded structure, folded stability, physiological stability, and dynamics.