Department of Biology, University of Rochester, 326 Hutchison Hall, Rochester NY 14627, USA.
Curr Top Med Chem. 2013;13(19):2397-406. doi: 10.2174/15680266113136660168.
Prion diseases are a group of fatal neurodegenerative diseases caused by the misfolding of cellular prion protein (PrP(C)) into pathogenic conformers (PrP(Sc)). 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 PrP(Sc) 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 PrP(Sc) conformers. The plasticity of prion conformers makes PrP(Sc) a particularly challenging drug target and suggests that combination drug therapies or targeting of PrP(C) 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.
朊病毒病是一组由细胞朊蛋白（PrP(C)）错误折叠成致病性构象（PrP(Sc)）引起的致命神经退行性疾病。尽管目前尚无有效的朊病毒病治疗方法，但已经鉴定出许多能够减少或消除朊病毒感染细胞中 PrP(Sc)的小分子抑制剂。然而，最近的实验表明，在持续治疗下，朊病毒有能力进化成耐药构象。这些研究表明，朊病毒株适应的机制涉及罕见的构象转换，然后在异质的 PrP(Sc)构象混合物中进行竞争选择。朊病毒构象的可塑性使得 PrP(Sc)成为一个特别具有挑战性的药物靶点，并表明可能需要联合药物治疗或靶向 PrP(C)才能进行有效的治疗。在这篇综述中，我们强调了最近的文献，这些文献证明了朊病毒耐药性和株特异性的现象，并讨论了针对朊病毒病治疗努力的潜在影响。
