Team 6 – Beta-sheet breakers

Medchem and Chemical biology approach

Medchem and Chemical biology approach

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ONCO & NEUROCHEMISTRY

Beta-sheet breakers

Beta-sheet breakers

All neurodegenerative diseases shared common hallmarks such as protein aggregates. Understanding the mechanism of fibrillation of Amyloid β, tau and alpha-synuclein is still in progress for the development of therapeutics for neurodegenerative diseases.

Our objective is to design tools to access to mechanistic aspects of aggregate formation. The main idea is to build new polyphenol derivatives (Azobenzene type) that can be photoswitched between two reversible OFF/ON states and apply them in the field of optopharmacology.

Designed compounds in their OFF state would interact with oligomers/fibrils/aggregates and upon photoswitching to more structurally constrain ON state therefore being able to break by enhancing distance between aggregates. They would constitute original ß-breakers but, they are also designed to be used to investigate aggregation/disaggregation mechanisms based on their reversibility giving access to accurate kinetic studies. This will represent an original tool to follow time-resolved locking/unlocking of oligomerization/fibrillation/ aggregation tested with ß-amyloid, α-synuclein and Tau protein in vitro (in solution and in cellulo) to establish a proof of concept, and, if promising, in vivo thanks to spatial and temporal control of our molecules.

This project will be developed by combining expertise in photoswitchable organic compounds monitored by NMR, organic and medicinal chemistry in the field of neurodegenerative diseases.