Ok Google, how could I design therapeutics against prion diseases?

Abstract

A number of previous successful attempts in the search for therapeutics for a variety of human pathologies highlight the importance of computational technologies in the drug discovery pipeline. This approach, often referred to as computer-aided drug design, is unfortunately inapplicable when the precise information regarding the three-dimensional structure of disease-associated proteins or the mechanism by which they are altered to generate misfolded isoforms are missing. A typical example is represented by prion diseases, fatal pathologies of the nervous system characterized by the conformational conversion of a physiological protein called PrP^C into a misfolded and infectious isoform referred to as PrP^Sc. Missing information regarding the atomic structure of PrP^Sc as well as the mechanism of templated conversion of PrP^C has severely halted the discovery of effective therapies for prion diseases. In this manuscript, we review emerging opportunities to apply computer-aided techniques to target PrP^C, PrP^Sc or to design inhibitors of prion replication, and discuss how these fast-evolving technologies could lay the groundwork for the application of entirely novel rational drug design schemes for these devastating pathologies.