Polyanions to tune the supramolecular assembly of amyloid-forming peptides – SUPRAMY

Amyloid-related diseases are widespread and obey to a common mechanism: the supramolecular self-assembly of a disease-related amyloid-forming peptide (e.g. the amyloid-ß in Alzheimer and IAPP in type 2 diabetes). Polyanions (natural polyphosphates –PP- and synthetic polyoxometalates –POM-) have been shown to lessen the toxicity associated to the peptide supramolecular edifices by tuning their self-assembly while the mechanism of action remains to be fully elucidated. This is the main objective of the SUPRAMY proposal that will make use of a set of advanced and complementary characterization tools to reveal how PP and POM modulate the Aß and IAPP self-assembly. This includes various physicochemical and biophysical methods and paramagnetic and solid-state NMR. This basic knowledge is required to guide further research lines of therapeutic purposes.
SUPRAMY is organized along four work-packages aiming (i) at identifying and delineating the conditions under which the self-assembly of Aß and IAAP is finely tuned by the polyanions PP and POM, and at selecting the most potent PP and/or POM able to do so and (ii) at studying the interactions between PP and/or POM and the peptides along the self-assembly process, with a set of complementary spectroscopic and analytical multi-scale methods. SUPRAMY will deliver key fundamental data (thermodynamic and kinetic parameters) regarding the self-assembly of amyloid-forming peptides and how they can be tuned by natural (PP) or synthetic (POM) polyanions. Beyond electrostatic interactions expected for the PP, POM will widen the range of possible interactions with the peptide, in particular for metal-substituted POM, where coordination bonds are also at play. Such basic parameters are needed to understand peptides self-assembly and to overcome the bottleneck in drug discovery that such process represents. Hence SUPRAMY aspires at providing upstream approaches to tackle medical and societal issues. To do so, the SUPRAMY consortium gathers experts from self-assembly of amyloid-forming peptides, inorganic chemistry of POM, and solution and solid-state NMR.