235 | Phthalocyanines as Molecular Scaffolds to Block Disease-Associated Protein Amyloid Aggregation: The case of α-Synuclein

Neurochemistry and Neuropharmacology

Author: Hugo Alejandro Garro | Email: hgarro@unsl.edu.ar

Hugo Alejandro Garro , Esteban Panozzo Zenere , Francisco Hita , Phelippe do Carmo Gonçalves , Claudio Fernàndez

1° Max Planck Laboratory for Structural Biology, Chemistry, and Molecular Biophysics of Rosario (MPLbioR, UNR-MPINAT), Partner Laboratory of the Max Planck Institute for Multidisciplinary Sciences (MPINAT, MPG). Centro de Estudios Interdisciplinarios, Universidad Nacional de Rosario, Rosario, Argentina.

Parkinson´s disease (PD) is the second most common age-related neurodegenerative disorder, affecting millions of people worldwide. α-Synuclein (αSyn) is a highly soluble, intrinsically disordered protein that is abundantly expressed in the brain and predominantly localizes to presynaptic terminals, in close proximity to synaptic vesicles. Since misfolding and amyloid aggregation of αSyn is thought to play a critical role in PD, the aggregation pathway of the protein represents then an obvious target for therapeutic intervention in this disorder. Therefore, understanding the molecular events behind αSyn amyloid assembly and its inhibition is of high clinical importance. In this context, the discovery of small molecules targeting disease-associated protein aggregation is considered one of the most active therapeutic approaches. From the screening of large libraries of small molecules, potential candidates with different chemical structures were found to modulate the aggregation of distinct amyloid proteins. Notably, poly-aromatic scaffolds belonging to polyphenols and porphyrinoids were predominantly identified by these screenings. Particularly, phthalocyanines were shown to exhibit anti-scrapie activity and inhibition of αS, tau, and Aβ amyloid assembly. In this work, we report at a residue specific level of resolution the structural and molecular basis for the inhibitory mechanism of a phthalocyanine molecule on ?s fibril amyloid assembly.