D-008 | Targeting the master-controller sequence motifs of α-Synuclein aggregation: Using small molecules as structural probes

Cellular and Molecular Neurobiology
Author: Irina Fernández | Email: ifernandez@cei-mplbior.unr.edu.ar

Irina Fernández^1°, Christian Griesinger^2°, Claudio O. Fernandez^1°2°,  Phelippe do Carmo Gonçalves^1°

^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.
^2° Max Planck Institute for Multidisciplinary Sciences, Department of NMR-based Structural Biology, Am Fassberg 11, 37077 Göttingen, Germany.

The aggregation of proteins into toxic conformations plays a critical role in the development of different neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). These disorders share a common pathological mechanism that involves the formation of aggregated protein species including toxic oligomers and amyloid fibrils. The aggregation of alpha-synuclein (αS) in PD results in neuronal death and disease onset. Accordingly, the aggregation pathway of this protein represents a useful target for therapeutic intervention. The design of small molecules that efficiently inhibit the aggregation process and/or neutralize its associated toxicity constitutes a promising tool for the development of therapeutic strategies against this disorder. In that direction, the limited number of amyloid inhibitors that have progressed through clinical trials could be explained by three main factors: (i) the complexity of the structural conversions occurring during the amyloid aggregation process, (ii) the absence of high-resolution structural information about the binding modes and nature of the molecular interactions involved in protein-inhibitor complexation, and (iii) the scarcity of research intended to understand the physicochemical requirements of inhibitory molecules determining their anti- amyloid activity. In this work, we explore several of these aspects related to amyloid inhibitors with poliaromatic scaffolds and their potential use as drug candidates in P