A wide range of observations in humans and animals indicate that a reduction in steady-state levels of the cellular prion protein (PrP^C) is both safe and may extend survival of prion diseases.

We recently discovered that PrP^C binds to sodium-potassium ATPases (NKAs), leading us to hypothesize that targeting NKAs with their natural inhibitors, cardiac glycosides (CGs), may cause cells to internalize and degrade NKAs and PrP^C. We tested this hypothesis and sought to identify a novel CG that exhibits lower toxicity and improved blood brain barrier (BBB) penetrance, relative to oleandrin, widely considered the best CG for brain applications. Atomic structures of NKAs facilitated predicting the binding poses of candidate CGs within human NKAs. A subsequent in silico screen identified a small number of CG, which we validated biochemically for the proposed application.

We will present data, which establish that CG exposure of human neural cell models causes the anticipated reductions in steady-state levels of PrP^C. Moreover, we have identified KDC203 as a CG that can reduce PrP^C levels in human neurons and astrocytes by >85%. In pilot in vivo work KDC203 exhibited lower toxicity and higher BBB penetrance than oleandrin, establishing this compound to be tenfold to 1000-fold more potent than other small-molecule compounds reported to date for this application.