Successes and challenges in phenotype-based lead discovery for prion diseases

J Med Chem. 2014 Aug 28;57(16):6919-29. doi: 10.1021/jm5001425. Epub 2014 Apr 24.


Creutzfeldt-Jakob disease (CJD) is a rare but invariably fatal neurodegenerative disease caused by misfolding of an endogenous protein into an alternative pathogenic conformation. The details of protein misfolding and aggregation are not well understood nor are the mechanism(s) by which the aggregated protein confers cellular toxicity. While there is as yet no clear consensus about how best to intervene therapeutically in CJD, prion infections can be propagated in cell culture and in experimental animals, affording both in vitro and in vivo models of disease. Here we review recent lead discovery efforts for CJD, with a focus on our own efforts to optimize 2-aminothiazole analogues for anti-prion potency in cells and for brain exposure in mice. The compounds that emerged from this effort were found to be efficacious in multiple animal models of prion disease even as they revealed new challenges for the field, including the emergence of resistant prion strains.

Publication types

  • Research Support, N.I.H., Extramural
  • Review

MeSH terms

  • Animals
  • Brain / drug effects
  • Brain / metabolism
  • Creutzfeldt-Jakob Syndrome
  • Disease Models, Animal
  • Drug Discovery / methods*
  • Drug Evaluation, Preclinical / methods*
  • Humans
  • Mice
  • Prion Diseases / drug therapy*
  • Structure-Activity Relationship
  • Thiazoles / chemistry
  • Thiazoles / pharmacology


  • Thiazoles
  • 2-aminothiazole

Grant support

National Institutes of Health, United States