A new inhibitor of protein aggregation associated with Parkinson’s disease from Dmytro Yushchenko Group

Parkinson's disease is the second most common neurodegenerative disease, affecting approximately 1 % of people over the age of 65. It is characterized primarily by the loss of dopaminergic neurons in a brain region called the substantia nigra, leading to movement disorders. To date there are no approved disease‐modifying therapies for Parkinson’s disease and the available treatments are only symptomatic, most of them being focused on the compensation of neurodegeneration.

Although the precise causes of cell death are unknown, the misfolding and aggregation of the abundant neuronal protein α-synuclein (αSyn) are involved in the pathogenesis of the disease. Most approaches for the inhibition of αSyn fibril formation are based on stabilizing the native monomeric form of the protein or destabilizing the fibrillized misfolded form. They require high concentrations of inhibitor and therefore cannot be easily used for therapies.

Dr. Volodymyr Shvadchak, Kseniia Afitska, and Dr. Dmytro Yushchenko from IOCB Prague designed a first inhibitor (Inh-β) that selectively binds the growing ends of αSyn fibrils and creates steric hindrance for the binding of monomeric αSyn. This approach permits the inhibition of fibril formation at Inh-β concentrations much lower than the concentration of monomeric αSyn (IC50 = 850 nm). The researchers studied its kinetic mechanism in vitro and identified the reactions that limit inhibition efficiency. They showed that blocking of αSyn fibril ends is an effective approach to inhibiting fibril growth and provides insights for the development of effective inhibitors of αSyn aggregation.

Volodymyr V. Shvadchak, Kseniia Afitska, Dmytro A. Yushchenko:
Inhibition of α-Synuclein Amyloid Fibril Elongation by Blocking Fibril Ends.
Angewandte Chemie International Edition 57 (20): 5690-5694 (2018).