Reversion of prion protein conformational changes by synthetic beta-sheet breaker peptides

Background Transmissible spongiform encephalopathies are associated with a structural transition in the prion protein that results in the conversion o f the physiological PrPc to pathological PrPSc. We investigated whether thi s conformational transition can be inhibited and reversed by peptides homol ogous to the PrP fragments implicated in the abnormal folding. which contai n specific residues acting as beta-sheet blockers (beta-sheet breaker pepti des). Methods We studied the effect of a 13-residue beta-sheet breaker peptide (i PrP13) on the reversion of the abnormal structure and properties of PrPSc; purified from the brains of mice with experimental scrapie and from human b eings affected by sporadic and variant Creutzfeldt-Jakob disease. In a cell ular 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 influenc e of the peptide on prion infectivity was studied in vivo by incubation tim e assays in mice with experimental scrapie. Findings The beta-sheet breaker peptide partly reversed in-vitro PrPSc to a biochemical and structural state similar to that of PrPc. The effect of th e peptide was also detected in intact cells. Treatment of prion infectious material with iPrP13 delayed the appearance of clinical symptoms and decrea sed infectivity by 90-95% in mice with experimental scrapie. Interpretation beta-sheet breaker peptides reverse PrP conformational chang es implicated in the pathogenesis of spongiform encephalopathies, These pep tides or their derivatives provide a useful tool to study the role of PrP c onformation and might represent a novel therapeutic approach for prion-rela ted disorders.