Transmissible spongiform encephalopathies are associated with a structural transition in the prion protein that results in the conversion of the physiological PrP^C to pathological PrP^Sc. We investigated whether this conformational transition can be inhibited and reversed by peptides homologous to the PrP fragments implicated in the abnormal folding, which contain specific residues acting as b-sheet blockers (b-sheet breaker peptides).

We studied the effect of a 13-residue b-sheet breaker peptide (iPrP13) on the reversion of the abnormal structure and properties of PrP^Sc purified from the brains of mice with experimental scrapie and from human beings affected by sporadic and variant Creutzfeldt-Jakob disease. In a cellular model of familial prion disease, we studied the effect of the peptide in the production of the abnormal form of PrP in intact cells. The influence of the peptide on prion infectivity was studied in vivo by incubation time assays in mice with experimental scraple.

The b-sheet breaker peptide partly reversed in-vitro PrP^Sc to a biochemical and structural state similar to that of PrP^C. The effect of the peptide was also detected in intact cells. Treatment of prion infectious material with iPrP13 delayed the appearance of clinical symptoms and decreased infectivity by 90–95% in mice with experimental scrapie.

β-sheet breaker peptides revrse PrP conformational changes implicated in the pathogenesis of spongiform encephalopathies. These peptides or their derivatives provide a useful tool to study the role of PrP conformation and might represent a novel therapeutic approach for prion-related disorders.