Foldzymes, Foldamers targeting Catalytic Activity – FAC

the carbocyclisation reaction of zinc enolates derived from N-(homoallyl)-amino esters and N-(allyl)-ß-amino esters have been chosen to acess to substituted prolines and beta-prolines derivatives.
Different size oligomers have been prepared by SPPS and studied by CD, NMR and mechanistic calculations.

Monomers derived from beta-prolines are not good candidats for the foldzymes building, in contrary to 3-substituted prolines.
These tools appears to be useful for the design of a PPII-Loop-PPII scaffold that we will use to the rational design of our foldzymes.

We have planed the synthesis of rationally design foldzymes in order to mimic the catalytic activity of a protease.

1. C. Caumes, N. Delsuc, R. Beni Azza, I. Correia, F. Chemla, F. Ferreira, L. Carlier, A. Perez Luna, R. Moumné, O. Lequin, P. Karoyan New J. Chem., 2013, 37, 1312-1319.
2. 3-Substituted Prolines: From Synthesis to Structural Applications, from Peptides to Foldamers C. Mothes, C. Caumes, A. Guez, H. Boullet, T. Gendrineau, S. Darses, N. Delsuc, R. Moumné, B. Oswald, O. Lequin, P. Karoyan Molecules, 2013, 18 (2), 2307-2327.

The unique properties of enzymes which stem from their well-defined three-dimensional structures have been a source of inspiration for the de novo construction of modular catalysts able to perform various reactions and enabling chemical selectivity However, in contrast to biopolymers catalysts, synthetic catalysts must often be designed for nonbiological transformations to be performed under conditions incompatible with retention of biopolymer structure and activity. Few examples of synthetic oligomers made of natural a-amino acids able to catalyze reactions have been reported, probably because of the difficulty to predict and control their conformation, and in the mean-time introduce functional groups in appropriate positions to perform catalysis. In this context, considerable progress has been made in the design of various types of foldamers -unnatural oligomers that fold into well-defined secondary structures in solution- such as peptoids, oligoureas, oligo(phenyleneethynelene), ?- or ß-peptides. Although foldamers have been explored for biomedical applications (peptidomimetics and proteinomimetics design, inhibition of microbial growth, design of cell penetrating peptides), their potential as catalysts has received poor attention.
The aim of this fundamental project is to develop foldamers with catalytic activity, based on new ß-amino acids oligomers. We propose to develop foldamers able to catalyse reactions in water, as do natural enzymes, and endowed with protease activity.
This interdisciplinary project will associate chemists, for developing new strategies for the syntheses of constrained and functionalized ß-amino acids and foldamers, structural biologists for the design and conformational studies of these foldamers bearing functional groups suitably oriented to perform catalysis in water and biochemists to investigate their catalytic properties.