A new class of polymer-peptide bioconjugates as self-assembly modulator – PP-SAM

Different strategies have been used to improve peptide properties. A first strategy is to synthesize peptidomimetics such as peptoids, ß-peptids, ?-peptids and peptide bond isosteres. Another commonly-used strategy is to synthesize polymer-peptide conjugates: a promising class of materials combining the functions and properties of native biomolecules and synthetic polymers in a single hybrid material generating unprecedented properties. The conjugation of a peptide with a suitably selected polymer enhances its properties by addressing some of its limitations such as lack of solubility, pH / T° sensitivity or quick degradation in (non) biological medium. These polymer-peptide biohybrids are currently synthesized either by coupling a preformed end-functional polymer with a reactive moiety of a peptide or by chemical modification of a peptide to covalently attach a radical polymerization initiator and the subsequent radical polymerization. A third strategy is the N-substitution of peptides which is commonly used in medical chemistry to increase the resistance of a peptide sequence toward enzymatic degradation or to modify its conformation without modifying side chain groups. For example, N-methylated amino acids residues are commonly used to improve therapeutic activity and pharmaceutical profile. N-alkyl groups other than methyl are much rarer for N-substitution due to synthesis difficulties.
Despite the amide bond is universal being the only chemical moiety on all peptide residue, peptide bond had never been used as initiator for grafting from polymerization until our recent paper. Its use as ubiquitous binding site combined with anionic polymerization paves the way to currently unachievable architectures combining polymer-peptide conjugate strategy with the N-substitution strategy. To achieve this goal, we can rely on recently published results in which we demonstrated the ability of phosphazene superbases to turn very weakly protic amide or carbamate groups into unusual initiating sites for the anionic ring-opening polymerization. This new grafting from method can be directly applied to peptide bonds and carbamate protected amines and does not required the prior chemical modification of the peptide. In addition, unlike radical polymerization techniques, anionic polymerization allows the grafting of heteroatom-containing polymer backbones. The graft chains will be directly attached on the peptide backbone using the nitrogen atoms as attachment points resulting in unprecedented conjugates called "Polymer N-grafted Peptide".
In Task 1, fundamental studies will be carried out on protected amino acids and dipeptides in order to have a better understanding of the chemical mechanisms and to control the polymerization of different monomer families. The stability of the protecting groups and the regioselectivity of the initiation will also be evaluated. The N-grafted technique will be subsequently applied to model oligopeptides in order to modulate their self-assembly properties.
In Task 2, silk-derived ß-sheet forming sequences will be graft with polyether chains. Various architectures and grafting densities will be synthesized. ß-sheet forming sequences will be used as driving force to self-assemble otherwise random coiled poly(thio)ethers. The influence on the nanostructuration of the conjugate architectures and the grafting density will be evaluated.
In Task 3, the grafting from method will be extended to the modulation of the self-assembly of medically relevant peptides via macromolecular engineering in order to alter their overall pathological effect. A systematic study will be performed with ß-sheet forming sequences involved in fibrils and amyloid-ß plaque formation in link with Alzheimer's disease. The fine tuning of the conjugates will allow an in-depth investigation of the relationship between the conjugate structures, their self-organizing properties and their capacities to modulate the aggregation of other peptides.