Prion diseases are a group of fatal neurodegenerative diseases caused by the misfolding of cellular prion protein
(PrPC) into pathogenic conformers (PrPSc). Although no effective therapies for prion diseases are currently available, a
number of small molecule inhibitors have been identified that are capable of reducing or eliminating PrPSc in prion infected
cells. However, recent experiments have shown that upon sustained treatment, prions have the capacity to evolve
into drug resistant conformations. These studies suggest that the mechanism of prion strain adaptation involves rare conformational
conversions followed by competitive selection among the heterogeneous pool of PrPSc conformers. The plasticity
of prion conformers makes PrPSc a particularly challenging drug target and suggests that combination drug therapies
or targeting of PrPC may be required for effective therapy. In this review, we highlight recent literature that demonstrate
the phenomenon of prion drug resistance and strain specificity, and discuss potential ramifications for therapeutic efforts
against prion diseases.
Keywords: Prion diseases, drug discovery, anti-prion drugs, drug resistance, strain specificity.
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