The formation of protease-resistant prion protein (PrP-res or PrP Sc ) involves selective interactions between PrP-res and its normal protease-sensitive counterpart, PrP-sen or PrP C . Previous studies have shown that synthetic peptide fragments of the PrP sequence corresponding to residues 119 -136 of hamster PrP (Ha119 -136) can selectively block PrP-res formation in cell-free systems and scrapie-infected tissue culture cells. Here we show that two other peptides corresponding to residues 166

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... -179 (Ha166 -179) and 200 -223 (Ha200 -223) also potently inhibit the PrP-res induced cell-free conversion of PrP-sen to the protease-resistant state. In contrast, Ha121-141, Ha180 -199, and Ha218 -232 were much less effective as inhibitors. Mechanistic analyses indicated that Ha166 -179, Ha200 -223, and peptides containing residues 119 -136 inhibit primarily by binding to PrP-sen and blocking its binding to PrP-res. Circular dichroism analyses indicated that Ha117-141 and Ha200 -223, but not non-inhibitory peptides, readily formed high ␤-sheet structures when placed under the conditions of the conversion reaction. We conclude that these inhibitory peptides may mimic contact surfaces between PrP-res and PrP-sen and thereby serve as models of potential therapeutic agents for transmissible spongiform encephalopathies.