Abstract
Decades of research efforts have conclusively provided overwhelming evidence that the cellular prion protein (PrPC) plays a central role in prion diseases, a set of fatal and incurable neurodegenerative disorders for which no therapy is yet available. In this Viewpoint, we provide an overview of the drug discovery strategies in the field, highlighting the current therapeutic hypotheses targeting, whether directly or indirectly, PrPC as well as the antiprion agents closest to clinical application.
Highlights
Prion diseases are rare, progressive, and incurable neurological disorders that naturally afflict both humans and animals, with the former including Creutzfeldt−Jakob disease, fatal familial insomnia, and Gerstmann−Straü ssler−Scheinker disease
Decades of research efforts have determined that these disorders share a common molecular mechanism, which is the conformational conversion of the GPI-anchored, properly folded cellular prion protein (PrPC) into an infectious misfolded self-replicating form (PrP scrapie, PrPSc) that accumulates in the brain of affected individuals.[1]
The strong scientific evidence confirming PrP as the central player suggests that any therapeutic strategy for prion diseases potentially able to affect PrPC and/or PrPSc, through direct or indirect mechanisms, is worthy of investigation
Summary
A fourth strategy currently explored to prevent both prion replication and toxicity is the relocalization of PrPC from the cell surface to intracellular compartments.[18] since PrPSc needs cell membrane PrPC molecules for its propagation, removal of the protein substrate can negatively affect both prion infectivity and activation of PrPC-mediated neurotoxic signaling.[19] A number of compounds have been described as able to redirect PrPC, including chlorpromazine (4) This molecule was initially thought to operate as PrPC binder, but recent studies clarified that it acts on the clathrin-mediated endocytosis altering the PrPC cell surface distribution to what has been observed for specific inhibitors targeting of the GTPase activity of dynamins.[20] the effects on the relocalization of PrPC were observed at concentrations only slightly lower than those causing cytotoxicity, and this behavior could reflect a possible intrinsic propensity of 4 and dynamin inhibitors to induce the intracellular rerouting of multiple surface proteins, thereby affecting cell viability.
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