Fluorinated foldamers: synthesis, structuration and capacity to interact with amyloid proteins and biomembranes – FluFOLD

FluFOLD aims to design and synthesize fluorinated peptidomimetic foldamers which have so far been under-explored in organic chemistry and unexploited in medicinal chemistry. The effects of the rational assembling of specific and original fluorinated amino acids in foldamers will be evaluated for their ability to: i. mimic the structuration of ?/3-10 and polyproline 2 (PP2) helices, ?-strands and ?-sheets; ii. increase their stability toward proteolysis; iii. interact with amyloid proteins to inhibit their pathological aggregation; iv. interact with biomembranes and promote the blood-brain barrier and biomembrane permeability. Organic, medicinal, and computational methods as well as biophysical and biological tools will be combined to obtain reliable information about the molecular and structural requirements to acquire anti-aggregation both in solution and in the presence of lipids and model membranes, and to cross biomembranes. As a proof of concept, we will target A?1-42, ?-synuclein and hIAPP amyloid proteins, involved in Alzheimer’s disease, Parkinson’s disease and type 2 Diabetes, respectively. This study will constitute the first example of considering the interest of all the different mimics of the canonical conformations (3-10/?-helical, ?-strand/?-sheet and PP2 helix) on anti-aggregant activities and on membrane interaction and permeability at the same time. Targeting the ?-sheet structures of amyloid proteins has been essentially reported as they are described to mainly constitute the pathological aggregates. Our rational design of mimics of specific secondary structure, based on specific fluorinated amino acids and on specific amino acid sequences of each amyloid protein will contribute to a better knowledge of the role and implication of ?-sheet structures but also of the other structuration (?/3-10 and PP2 helices) of amyloid proteins, that have been only recently reported as possible key intermediates in the amyloid cascade.