A tetracationic porphyrin with dual anti-prion activity

Prions are deadly infectious agents made of PrP^Sc, a misfolded variant of the cellular prion protein (PrP^C) which self-propagates by inducing misfolding of native PrP^C. PrP^Sc can adopt different pathogenic conformations (prion strains), which can be resistant to potential drugs, or acquire drug resistance, hampering the development of effective therapies. We identified Zn(II)-BnPyP, a tetracationic porphyrin that binds to distinct domains of native PrP^C, eliciting a dual anti-prion effect. Zn(II)-BnPyP binding to a C-terminal pocket destabilizes the native PrP^C fold, hindering conversion to PrP^Sc; Zn(II)-BnPyP binding to the flexible N-terminal tail disrupts N- to C-terminal interactions, triggering PrP^C endocytosis and lysosomal degradation, thus reducing the substrate for PrP^Sc generation. Zn(II)-BnPyP inhibits propagation of different prion strains in vitro, in neuronal cells and organotypic brain cultures. These results identify a PrP^C-targeting compound with an unprecedented dual mechanism of action which might be exploited to achieve anti-prion effects without engendering drug resistance.