Abstract EN:

Prions diseases are fatal neurodegeneratives disorders, which affect both humans and animals. No early diagnosis test of prions as well as effective treatment exists. The infectious agent consists mainly of the abnormal form, named PrPSc of the cellular protein prion, PrPC. Even if the replication cycle of prions is not totally known, the majority of the therapeutic strategies target monomerics forms of PrPC, PrPSc as well as amyloid fibrils. Dimers or trimers of PrPSc were recently described and would be part of an unstable preamyloïde state. We hypothesize that the identification of small molecules interacting with those preamyloid intermediates would block the replication cycle of prions and thus would reduce their infectivity. For this purpose, we used an approach of virtual screening, followed by a cellular screening on prions infected-cells. We identified a family of thienyls pyrimidines and azines compounds, able of stabilizing dimers of PrPSc, and observable in denaturing conditions by immunoblot. In vivo studies indicate that the pre-incubation of compounds with infected brain homogenate, reduces the prion infectiosity of the inoculum, suggesting a potential therapeutic application. We also studied the mechanism of action of these molecules and we propose that these compounds could directly interact with prions via a mechanism of aggregation. We showed that thienyl pyrimidine compounds can discriminate the infected brain homogenates from healthy ones, by the presence of specific PrPSc dimers, suggesting a potential application for the development of a new diagnosis test for ESST