Developing Pharmacological Degraders for the Cellular Prion Protein

Prion diseases are rare, fatal neurodegenerative disorders for which no cure currently exists. The scientific community has put in significant effort to find potential treatments; however, no effective drugs are available on the market yet. In the searching for new, unconventional approaches for tackling this disease, recent research has shown that it is possible to target not the native form of the prion protein, but rather a folding intermediate. This led to the discovery of a new small molecule degrader referred to as SM875. In this work, we explore the chemical space of this molecule through a qualitative structure-activity relationship analysis. This approach has allowed us to to identify which features of the molecule can be modified to enhance its activity and to gain deeper insights into the structure of the target pocket. Additionally, various studies have been conducted aiming to provide structural evidence for the binding interaction between the folding intermediate of PrP and SM875. This included experiments conducted in orbit aboard the International Space Station, along with various mass spectrometry analyses. Finally, we performed new biological screenings of both synthetic compounds and natural raw extracts. This has expanded our options for discovering new scaffolds that are active against PrP, employing both traditional mechanisms of action and innovative degrader approaches.