Photoresponsive Prion‐Mimic Foldamer to Induce Controlled Protein Aggregation

Abstract

Proteins reconfigure their 3D‐structure, and consequently their function, under the control of specific molecular interactions that sense, process and transmit information from the surrounding environment. When this fundamental process is hampered, many pathologies occur as in the case of protein misfolding diseases. In this work, we follow the early steps of α‐synuclein (aS) aggregation, a process associated with Parkinson's disease etiopathogenesis, that is promptly promoted by a light‐mediated binding between the protein and a photoactive foldamer. The latter can switch between two conformations, one of which generates supramolecular fibrillar seeds that act as molecular templates able to induce a fast β‐sheet transition for aS monomers that successively undergo fibrillar polymerization. The proposed method represents a powerful tool to study protein aggregation relevant to misfolding diseases in a controlled and inducible system.

A 2D Fragment-Assisted Protein Mimetic Approach to Rescue α-Synuclein Aggregation Mediated Early and Post-Disease Parkinson’s Phenotypes

“…The aggregation of αS is associated with the impaired DA neurons, which is a pathological hallmark of PD [12][13][14][15][16][17][18] . Therefore, one of the potential disease-modifying therapeutic strategies for PD is the modulation of αS aggregation [19][20][21][22][23][24][25][26][27][28][29] . A few small molecules have been shown to inhibit αS aggregation 19-29 (ref.…”

“…within 19); however, some of them have complex chemical structures, which might limit their ability for synthetic tuning and further optimization of the antagonist activity against αS aggregation. Also, protein mimetics have been identified to inhibit αS aggregation; however, the chemical space on them was limited and there was no systematic optimization carried out against αS aggregation [23][24][25][26][27][28][29] . Moreover, most of these ligands were not tested against PD phenotypes in DA neurons in in vivo models to further assess their therapeutic potential [23][24][25]28,29 .…”

“…Also, protein mimetics have been identified to inhibit αS aggregation; however, the chemical space on them was limited and there was no systematic optimization carried out against αS aggregation [23][24][25][26][27][28][29] . Moreover, most of these ligands were not tested against PD phenotypes in DA neurons in in vivo models to further assess their therapeutic potential [23][24][25]28,29 . Therefore, ligands with the ability to manipulate aggregation with a large chemical space and having the tendency for systematic optimization of the antagonist activity could lead to potent antagonism of αS aggregation.…”