NaDyPe · Native Dynamic Peptides: application to the preparation of self-replicating peptides and dynamic proteins using dynamic combinatorial chemistry

A Dynamic combinatorial library (DCL) is formed by the interconnection of building blocks by reversible covalent or non-covalent bonds. In such DCL, all possible combinations of the initial constituents may form, in proportions specific to the thermodynamic equilibrium of the system. Disruption of this equilibrium by physical or chemical factors, may lead to adaptation through amplification of one or more constituents of the library by rearrangement of its components. This dynamic combinatorial chemistry (DCC) approach has been successfully used in the 15 past years, in particular for the discovery of drugs selected by the biological target itself by in situ molecular recognition.In this project, we want to implement the DCC concept towards native peptide chemistry. Our main objective is to create a new class of constitutionally dynamic peptide that would combine the structural, catalytic, and (bio)recognition properties of peptides, or proteins, with the adaptive character of constitutionally dynamic assemblies.The objectives of the present research project are threefold. The first is to pioneer a firmly original chemical methodology to make some peptidic bond reversible under physiological conditions. The second is to probe the applicability of this methodology for the preparation of self-replicating dynamic coiled-coil peptides. The third is to prepare a dynamic analog of streptavidin from a dynamic combinatorial library of small peptides.Such an achievement will open the door to the development of dynamic proteins that could adjust their composition and structure in response to a binding event. For instance, this approach may in principle allow the “self-fabrication” of dynamic enzymes, receptors or antibodies able to adapt their composition, in a chemically controlled evolution process, to fit their target (a substrate, a receptor on a cancer cell, or a pathogenic protein).