AbstractPrion diseases are rare neurodegenerative conditions associated with the conformational conversion of the cellular prion protein (PrP^C) into PrP^Sc, a self-replicating isoform (prion) that accumulates in the central nervous system of affected individuals. The structure of PrP^Sc is poorly defined and likely to be heterogeneous, as suggested by the existence of different prion strains. The latter represents a relevant problem for therapy in prion diseases, as some potent anti-prion compounds have shown strain-specificity. Designing therapeutics that target PrP^C may provide an opportunity to overcome these problems. PrP^C ligands may theoretically inhibit the replication of multiple prion strains, by acting on the common substrate of any prion replication reaction. Here, we characterized the properties of a cationic tetrapyrrole [Fe(III)-TMPyP], which was previously shown to bind PrP^C and inhibit the replication of a mouse prion strain. We report that the compound is active against multiple prion strains in vitro and in cells. Interestingly, we also find that Fe(III)-TMPyP inhibits several PrP^C-related toxic activities, including the channel-forming ability of a PrP mutant and the PrP^C-dependent synaptotoxicity of amyloid-β (Aβ) oligomers, which are associated with Alzheimer’s Disease. These results demonstrate that molecules binding to PrP^C may produce a dual effect of blocking prion replication and inhibiting PrP^C-mediated toxicity.