Foldamer approaches to enzyme engineering and mimicry – FOLDINGUE

Mimicking and engineering efficient biomimetic processes have been a long-standing goal of the scientific community. In particular, access to artificial enzymatic systems enabling complex chemical transformations to be performed is one major challenge. Indeed, broadening enzyme reactivity to transformations never seen in nature, increasing solvent and temperature stability, incorporating transition metals into the active site of protein scaffolds, as well as expanding substrate scope and reaction selectivity (enantio-, diastereo-, regio-, and chemoselectivity) are the key features of biocatalysts to address challenges in synthetic organic chemistry that cannot be solved with traditional small molecules or ligand-bound transition metal catalysts. Synthetic folded oligomers (also called foldamers) have the potential for breakthrough in this direction. However, attempts to interface these systems with enzymes and/or to reproduce enzymatic activities have remained limited thus far. In the last decade, the group of Gilles Guichard has pioneered the development and the structural characterization of a new class of peptidomimetics, the aliphatic N,N’-linked oligoureas, and highlighted the remarkable compatibility of their backbones with a-peptides demonstrating thus the potential of interfacing natural peptides and urea-based backbones to create composite protein structures. The presence of the urea residues in the sequence brings additional level of conformational control over a–peptides as well as new functionalities, while a–amino acids residues brings the side chain diversity at low cost.

In this project, we aim to engineer synthetic enzyme-based and enzyme-like architectures using oligourea foldamers in order to investigate their structures and explore their functions in terms of catalysis and chemical reactivity in aqueous environment. Two complementary approaches will be envisioned: (A) a foldamer-based protein prosthesis starting from the natural scaffold of ribonuclease A, that will consist in swapping a natural a–helical domain of the active site with helical oligourea-based foldamers, and (B) the de novo design of enzyme mimics using supramolecular assemblies of water soluble foldamers. The main purpose of this project will be to investigate thermodynamic aspects of chimeric helix molecular recognition processes and their impact on overall protein folding, as well as to exploit the potential of foldamer subunits for catalysis.

The well-established expertise of the group in oligourea-based foldamer chemistry associated with the specific skills of the scientific coordinator in synthesis, catalysis and peptidomimetic chemistry will create thus a good synergy to carry out such a research project. The high-level and interdisciplinary environment in terms of technical facilities and expertise available both at CBMN and IECB will enable the design and synthesis part, but also the structural, biophysical and biochemical studies to be performed in a suitable environment.