Abstract: PrPSc, a misfolded, aggregation-prone isoform of the cellular prion protein (PrPC ), is the infectious prion agent responsible for fatal neurodegenerative diseases of humans and other mammals. PrPSc can adopt different pathogenic conformations (prion strains), which can be resistant to potential drugs, or acquire drug resistance, posing challenges for the development of effective therapies. Since PrPC is the obligate precursor of any prion strain and serves as the mediator of prion neurotoxicity, it represents an attractive therapeutic target for prion diseases. In this minireview, we briefly outline the approaches to target PrPC and discuss our recent identification of Zn(II)-BnPyP, a PrPC -targeting porphyrin with an unprecedented bimodal mechanism of action. We argue that in-depth understanding of the molecular mechanism by which Zn(II)-BnPyP targets PrPC may lead toward the development of a new class of dual mechanism anti-prion compounds.

Key words: anti-prion drug, anti-PrP^C antibody, antisense oligonucleotide, neurodegeneration, pharmacological chaperone, porphyrin, prion disease, PrP^C degrader, PrP^C shedding, zinc finger repressor