As many as 2% of people over 60 years of age develop Parkinson's disease, a condition that destroys areas of the brain that control movement. While the causes of the disease remain unknown, a protein known as alpha-synuclein, which is responsible for a range of duties in the motor areas of the brain, has emerged as an important research subject over the past 15 years.
In his research, Tommi Kilpeläinen, MSc (Pharmacy), who recently defended his doctoral thesis at the University of Helsinki’s Faculty of Pharmacy, has developed a new series of compounds for inhibiting the prolyl oligopeptidase (PREP) enzyme. The novel compounds were found to be considerably more effective than previous compounds in reducing the aggregation of alpha-synuclein, which is harmful to nerve cells, in cell cultures. PREP is an intracellular enzyme that occurs in the brain and elsewhere in the body, which affects alpha-synuclein aggregation.
“Relating to the compounds, we also discovered an entirely new drug candidate that acts through the PREP enzyme. Already in seven days, a therapy based on this compound significantly reduced alpha-synuclein aggregations in the areas of the brain responsible for movement in the mouse model. In fact, further development toward clinical trials seems possible based on the findings so far,” Kilpeläinen says.
A protein that causes defective forms, accumulation and cell death
Alpha-synuclein is predisposed to defective forms that easily cling to each other. When such protein aggregations accumulate inside nerve cells, the cells die. Alpha-synucleins are also able to travel between cells and spread neuronal destruction in the brain.
Already prior to this, researchers have been able to reduce harmful alpha-synuclein aggregations in cell cultures and laboratory animal models by inhibiting the function of the PREP enzyme. At their best, PREP inhibitors helped eliminate motor disturbances altogether in animal models.
However, typical PREP inhibitors have not been found to be optimal in reducing harmful alpha-synuclein aggregations or accelerating their breakdown in cell cultures. Furthermore, the findings were achieved through non-patentable model compounds whose further development with pharmaceutical companies has been almost impossible.
Doctoral defense
Tommi Kilpeläinen, MSc (Pharmacy), defended his doctoral thesis entitled ‘Development and biological characterization of novel ligands for protein-protein interaction-based effects of prolyl oligopeptidase’ on 4 June 2021 at the Faculty of Pharmacy, University of Helsinki. The thesis is also available in electronic form through the Helda repository.