New Opportunities for Peptide Synthesis – NOPS

Peptides and proteins are essential biomolecules to sustain life, implicated in almost all physiological processes. Besides, these molecules are attracting increasing attention on different fields such as medicinal chemistry, polymers and materials science. Indeed, the number of peptide drug in clinical phases increases at a rate of 20% each year since 2010. While these molecules are naturally built up from the N-terminal end to the C-terminal end (N->C direction), they are chemically synthesized from the opposite direction (C->N). Indeed, the traditional synthesis proceeds through the activation of the carboxylic acid moiety of a first amino acid, by means of coupling reagents, allowing the nucleophilic attack of the amino partner of a second amino acid with concomitant formation of the amide bond. Although very efficient, these coupling reagent strategies suffer from several drawbacks, notably those associated with i) epimerization, ii) challenging fragment couplings and peptide cyclization, iii) cost and wasteful processes, iv) side-reactions during the basic activation step associated to particular amino acids.
The development of original processes based on non-classical activation (e.g. carboxylic acid acitivation) for amide bond formation could not only unlock major technological limitations on peptide synthesis but also provide alternative synthetic pathway to most of modern drug-like compounds. Indeed, the amide function is present in more than 25% of all marketed pharmaceuticals and its formation remains the main reaction used in medicinal chemistry.
In 2012, a project funded by the ANR program JCJC (NIPS) paved the way to an original procedure for the formation of amides on the basis of a novel mode of activation (e.g. amine instead of carboxylic acid activation). This “inverse activation” proceeds through the modification of the alpha-amine function instead of classical carboxylate activation of amino acids. The project “New Opportunities for Peptide Synthesis (NOPS)” starts from this solid proof-of-concept to explore a whole range of unprecedented possibilities offered by this new mode of activation towards innovative application into peptide chemistry.