The transformation of the cellular prion protein (PrPC) into the infectious form (PrPSc) is implicated in the invariably fatal transmissible spongiform encephalopathies. To identify a mechanism to prevent the undesired PrPC -> PrPSc transformation, we investigated the interactions of recombinant prion proteins with a number of potential therapeutic agents which inhibit the PrPSc formation, infectivity, and the accumulation of the misfolded form. We show that the prion aggregates formed in the presence of six compounds have no beta-structure, which is typical of the infectious form, and possess considerably higher alpha-helical content than the normal PrPC. The investigated compounds stimulate the formation of alpha-helices and the destruction of beta-structure. They prevent the transformation of alpha-helical structure into beta-sheets. Probably, this is the reason for the resistance to PrPC -> PrPSc transformation in the presence of these compounds. The results may be useful for the future therapy of neurodegenerative diseases. (c) 2006 Elsevier Inc. All rights reserved.