Therapeutic targeting of cellular prion protein: toward the development of dual mechanism anti-prion compounds

PrP Sc , a misfolded, aggregation-prone isoform of the cellular prion protein (PrP C ), is the infectious prion agent responsible for fatal neurodegenerative diseases of humans and other mammals. PrP Sc 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 PrP C 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 PrP C and discuss our recent identification of Zn(II)-BnPyP, a PrP C -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 PrP C may lead toward the development of a new class of dual mechanism anti-prion compounds.