Strain Specificity and Drug Resistance in Anti-Prion Therapy

Author(s): Lakshmi Miller-Vedam, Sina Ghaemmaghami

Journal Name: Current Topics in Medicinal Chemistry

Volume 13 , Issue 19 , 2013

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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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Article Details

Year: 2013
Page: [2397 - 2406]
Pages: 10
DOI: 10.2174/15680266113136660168
Price: $65

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