Synthesis, structural analysis and biological evaluation of new biomimetic systems with well-defined structures – BioMiSys

Proteins and peptides perform a wide range of functions in biological systems, nearly all of which require the polypeptide chain to adopt a compact and specific folding pattern. These folding patterns constitute the key of information and biological functions. However, the difficulty to synthesize protein and the intrinsic instability of peptides in vivo limit their potential in the drug discovery process. To overcome this problem, a new field of research has emerged and flourished thanks to the realization that chemical moieties with unique, non-biological backbones, known as foldamers, are also capable of higher-ordered structure and biological activity. Within the class of alpha-helical mimicking oligomers, the most common include amino acid derivatives such as beta-, gamma-peptides and peptoids. However, more recently nonpeptidic organic oligomers have received great attention due the wide variety of functional groups available in organic chemistry and the possible new physical and biological properties they can exhibit. These compounds provide useful tools for understanding the factors that govern the formation of three-dimensional structures in biopolymers, but also for designing new materials or therapeutic agents. The aim of BioMiSys project is to create new biomimetic systems with well-defined structures constructed from cyclic beta-amino acids and constrained dipeptide mimics developed in our research group. These scaffolds will be selected by molecular dynamic for their suitability to fold in ordered structures by oligomerization. The confirmed candidates will be synthesized to construct homo and /or hetero-oligomers of various lengths. Their structure will be further analysed and their biological activity will be evaluated. Actually, preliminary results obtained on our first synthesized oligomers are very encouraging and prompt us to extent this approach to a large set of compounds but also to develop a useful molecular modelling predictive tool. During our effort towards exploiting the biological potential of these first series of oligomers, we have shown that they allowed the translocation of a fluorescent probe into cells. The originality of these oligomers, in addition to afford a new class of cell delivering system, should help to elucidate the mechanism of translocation of this class of compounds. Though encouraging, much work remains toward the application of these compounds as functional drug delivery vectors and the understanding of their entry pathway and mechanism. All these results will prompt us, in a first instance, to carefully consider the structural properties of our different synthesized oligomers, but also to evaluate them as therapeutic vectors. However, our full ambition is to use them to construct: bioactive compounds (inhibitors of therapeutically relevant protein-protein or RNA–protein interactions, antimicrobial and antifungal compounds), artificial proteins (for example by replacing classical alpha-helical segments in proteins of known 3D structures by our structurated oligomers), nanostructures (artificial channels), biomaterials, elicitors able to increase natural plant defense.