Approaches for discovering anti-prion compounds: lessons learned and challenges ahead

Introduction: Recent years have witnessed major advances in our understanding of the molecular bases of prion diseases. These studies not only highlight the protein misfolding as a potential initiator of a neurodegenerative process, they also provide a foundation for considering whether such a process can be common to many neurodegenerative diseases, including Alzheimer's disease. This makes prion diseases a sort of prototype of neurodegenerative disease, endowed with some intrinsic positive features in terms of drug development. Thanks to the fact that disappearance of the scrapie protein can serve as a clear readout of drug efficiency, phenotypic approaches have high potential for prion disease drug discovery. Areas covered: In this review, the authors discuss phenotypic screening and how it lends itself to drug repositioning. Furthermore, they discuss the advantages of working with a molecule with proven safety, tolerability and drug-like properties in combination with a reliable phenotypic screening and how it could improve the success rate for prion drug development. They also provide examples of several interesting candidates that have been identified using this approach, including quinacrine, astemizole, guanabenz and doxycycline. Expert opinion: The availability of persistently scrapie-infected murine neuroblastoma cells has greatly helped to identify compounds that inhibit prion formation. However, a human neuronal model infected with the human isoform would ultimately serve as the ideal disease model toward the discovery of effective drugs.