My group has developed a radical new approach to creating large, complex molecules to carry out complex molecular recognition and catalytic functions in the way that biological proteins do. Our approach is to synthesize stereochemically pure cyclic building blocks (bis-amino acids) that we couple through pairs of amide bonds to create spiro-ladder oligomers with programmed shapes (bis-peptides).
Functionalized spiroligomers are efficiently assembled in solution or solid support using a new amide bond forming reaction that we have recently described (Brown, Z.Z. and Schafmeister, C.E., "Synthesis of hexa- and penta- substituted diketopiperazines from sterically hindered amino acids", Org. Lett., (2010) 12(7), 1436-1439). The structure of each spiroligomer is pre-organized and controlled by the sequence and stereochemistry of its component bis-amino acids. Spiroligomer structures range from short functionalized oligomers containing two or three bis-amino acids (500-700 Daltons) to complex covalent-bundles containing dozens of individually controllable stereocenters and functional groups that display complex three-dimensional structures and present pockets and complex surfaces (1,500 – 10,000 Daltons).
We have demonstrated that short spiroligomers have good water solubility, penetrate eukaryotic cells, and unlike peptides they will not be degraded by proteases.
We are developing spiroligomers to speed up chemical reactions (act as catalysts).
We are also developing spiroligomers as new therapeutics that can bind protein surfaces and disrupt protein-protein interactions.