Dr Salvador Ventura: Chemical Chaperones as Novel Drugs for Parkinson’s Disease



Orthogonal strategies such as drug repositioning, rational design, and high-throughput screening have identified molecules that target α‐synuclein (α-syn) aggregation, the central molecular event in Parkinson’s disease (PD).
The anti-aggregation compounds under development target the complete spectrum of α-syn conformers through different mechanisms: monomer stabilization, prevention of dimer formation, stabilization or disruption of oligomers, avoidance of secondary nucleation, and dismantling of fibrils.
The potential of particular molecules to halt neurodegeneration in PD is already being evaluated in clinical trials. If successful, they might benefit patients suffering from other α-synucleinopathies.
The development of biomarkers to allow evaluation of therapeutic efficacy will be necessary to accelerate and bring down the high cost of current clinical trials for PD.

Parkinson’s disease (PD) is characterized by progressive loss of dopaminergic neurons and the accumulation of deposits of α-synuclein (α-syn) in the brain. The pivotal role of α-syn aggregation in PD makes it an attractive target for potential disease-modifying therapies. However, the disordered nature of the protein, its multistep aggregation mechanism, and the lack of structural information on intermediate species complicate the discovery of modulators of α-syn amyloid deposition. Despite these difficulties, small molecules have been shown to block the misfolding and aggregation of α-syn, and can even disentangle mature α-syn amyloid fibrils. In this review we provide an updated overview of these leading small compounds and discuss how these chemical chaperones hold great promise to alter the course of PD progression.