Catalytic Foldamers

With proteins, Nature displays an enviable control of both structure (secondary, tertiary, quaternary)
and function (signaling, catalysis).  Foldamers, oligomers that adopt specific, compact conformations, have been shown to form several unnatural secondary and quaternary structures.  Using these well-defined structures, foldamers have demonstrated biological activity as anti-microbial agents and inhibitors of protein-protein interactions.  Here we describe the development of the first catalytic foldamers.  Employing a single, rigid scaffold and known imine/enamine chemistry, foldamers with unique sidechain functionalities have been found to catalyze a retroaldol and Michael reaction in an aqueous and organic environment, respectively.

                                      

This relatively new project has required the design and synthesis of novel b-amino acid monomers.  Peptide characterization and rate determination have involved analytical methods such as circular dichroism (CD), 1H NMR, MALDI-MS and UV-visible spectroscopy.  Current efforts are focused on developing bifunctional peptides in addition to expanding both their reaction and substrate scope.

 

3. "Evaluation of the Ser-His Dipeptide, a Putative Catalyst of Amide and Ester Hydrolysis." MacDonald, M.J.; Lavis, L.D.; Hilvert, D.; Gellman, S.H. Org. Lett. 2016, 18, 3518.

2. "A Rationally Designed Aldolase Foldamer," M. M. Müller, M. A. Windsor, W. C. Pomerantz, S. H. Gellman and D. Hilvert Angew. Chem. Int. Ed. 2009, 48, 922.

1. "Nanofibers and Lyotropic Liquid Crystals from a New Class of Self-Assembling β-Peptides," W. C. Pomerantz, V. M. Yuwono, C. L. Pizzey, J. D. Har tgerink, N. L. Abbott and S. H. Gellman Angew. Chem. Int. Ed. 2008, 47, 1241.