Fragment screening against human prion protein

Abstract

Prion diseases are progressive neurodegenerative disorders that affect both humans and animals. They are associated with the conformational conversion of the cellular prion protein PrP into PrPSc, a self-replicating isoform (prion) that accumulates in the central nervous system of affected individuals. The mechanism underlying the PrP-to-PrPSc conversion and subsequent aggregation remains to be elucidated. At present, no specific therapeutic and prophylactic interventions are available for prion diseases. Compounds that stabilize the PrP health conformation represent a promising strategy to inhibit prion propagation. Due to lack of canonically druggable cavities in PrP, fragment screening emerges as unique technique to advance our knowledge of how and where to target PrP. This approach entails screening small libraries of very small molecules that follow the "rule of three" criteria and an efficient search of diverse chemical space. In our project, we propose to combine the state-of-art technology in X-crystallography fragment screening with biophysical and biochemical tools, to identify and validate compounds that are able to bind and stabilize the cellular form of PrP found in healthy organisms. Lead-to-drug optimization is a real possibility in case we succeed in identifying lead compounds. Potent candidates can be tested against cells infected with prions and animal model assays. This project will be performed in collaboration with Broad Institute at MIT and Harvard and Diamond Synchrotron source in UK, and represents an outstanding opportunity for our laboratory to aggregate new capabilities in medicinal chemistry and translational research. (AU)