The Compelling Demand for an Effective PrPC-Directed Therapy against Prion Diseases

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.

[1]  G. Legname,et al.  Novel regulators of PrPC expression as potential therapeutic targets in prion diseases , 2020, Expert opinion on therapeutic targets.

[2]  Jayme L. Dahlin,et al.  Multimodal small-molecule screening for human prion protein binders , 2020, The Journal of Biological Chemistry.

[3]  Yu Ding,et al.  Emerging New Concepts of Degrader Technologies , 2020, Trends in Pharmacological Sciences.

[4]  D. Rader,et al.  Antisense oligonucleotides for atherosclerotic disease , 2020, Nature Medicine.

[5]  E. Lander,et al.  Towards a treatment for genetic prion disease: trials and biomarkers , 2020, The Lancet Neurology.

[6]  S. Orioli,et al.  PHARMACOLOGICAL PROTEIN INACTIVATION BY TARGETING FOLDING INTERMEDIATES , 2020, bioRxiv.

[7]  C. Raggi,et al.  Small Molecules with Anti Prion Activity. , 2020, Current medicinal chemistry.

[8]  S. Schreiber,et al.  Antisense oligonucleotides extend survival of prion-infected mice , 2019, JCI insight.

[9]  Y. Matsuyama,et al.  A designer molecular chaperone against transmissible spongiform encephalopathy slows disease progression in mice and macaques , 2019, Nature Biomedical Engineering.

[10]  D. Harris,et al.  Identification of anti-prion drugs and targets using toxicity-based assays. , 2019, Current opinion in pharmacology.

[11]  C. Sigurdson,et al.  Cellular and Molecular Mechanisms of Prion Disease. , 2019, Annual review of pathology.

[12]  K. Kuwata,et al.  Oral toxicity study of an antiprion compound N,N’-[(cyclohexylmethylene)di-4,1-phenylene]bis[2-(1-pyrrolidinyl)acetamide] in rats and cynomolgus monkeys , 2019, Fundamental Toxicological Sciences.

[13]  D. Harris,et al.  Prions activate a p38 MAPK synaptotoxic signaling pathway , 2018, PLoS pathogens.

[14]  V. Cecchetti,et al.  Pharmacological Agents Targeting the Cellular Prion Protein , 2018, Pathogens.

[15]  I. Zerr,et al.  α-synuclein interacts with PrPC to induce cognitive impairment through mGluR5 and NMDAR2B , 2017, Nature Neuroscience.

[16]  R. Nonno,et al.  An antipsychotic drug exerts anti-prion effects by altering the localization of the cellular prion protein , 2017, PloS one.

[17]  R. Nonno,et al.  A cationic tetrapyrrole inhibits toxic activities of the cellular prion protein , 2016, Scientific Reports.

[18]  John W. Gilbert,et al.  Cellular Prion Protein Mediates Impairment of Synaptic Plasticity by Amyloid-β Oligomers , 2009, Nature.

[19]  R. Campbell,et al.  Imidazolyl benzimidazoles and imidazo[4,5-b]pyridines as potent p38alpha MAP kinase inhibitors with excellent in vivo antiinflammatory properties. , 2008, Bioorganic & medicinal chemistry letters.

[20]  S. Biocca,et al.  Selective re‐routing of prion protein to proteasomes and alteration of its vesicular secretion prevent PrPSc formation , 2007, Journal of neurochemistry.