Foldamer Chemistry

De novo design of synthetic objects with well-defined tertiary and quaternary structures mimicking functions of biomacromolecules represents an ultimate goal in biomimetic chemistry. The design of discrete biotic and abiotic oligomers (i.e. foldamers) with predictable and well-characterized folding patterns (e.g. secondary structure stabilized by remote intrastrand interactions, local conformational control or solvophobic effects) has attracted considerable attention over the last fifteen years.

Urea-oligomers : Structure Determination. In the past few years, we have investigated non-oligoamide oligomers consisting of urea bridging units and bearing proteinogenic side-chains. We found that enantiopure oligoureas of general formula [NH-CH(R)-CH2-NH-CO-]n show a remarkable propensity to fold into stable helical secondary structures reminiscent of the α-helix (Figure 1).

Figure 1 : Crystal structure of helical N;N’-linked oligoureas. a) stereoview of a nona-urea; b) View along the helical axis; c) Detail of the three-centered H-bonding.

From Structure to Function. We believe that the strong helix folding propensity, together with the diversity of available side chain appendages and resistance to protease degradation, makes the oligourea backbone a promising candidate for biomedical applications. For exemples, short sequences designed to mimic globally amphiphilic α-helical host-defense peptides display broad antibacterial activity with selectivity for prokaryotic versus mammalian red blood cell membranes

(Figure 2).

Figure 2 : Antibacterial oligoureas. Sequence of 8-mer oligourea designed to form an amphipathic helical structure and corresponding CD spectra in aqueous and lipidic environments showing the increased propensity for helix formation in the contact of phospholipids.

Selected Publications : Fischer & Guichard, Org. Biomol. Chem. 2010, in press; Fischer et al. Angew. Chem. Int. Ed. Engl. 2010, 49, 1067-1070; Claudon et al. Angew. Chem. Int. Ed. Engl. 2010, 49, 333-336; Guichard et al. Magn. Reson. Chem. 2008, 46, 918-924; Fischer et al. Org. Biol. Chem. 2008, 6, 2596–2610; Oakley et al. J. Phys. Chem. B, 2007, 111, 3274-3279; Violette et al. Chem. Eur. J. 2008, 14, 3874-3882; Violette et al. Chem. Biol., 2006, 13, 531-538; Violette et al. J. Am. Chem.Soc. 2005, 127, 2156-2164.