Discovery of a class of diketopiperazines as antiprion compounds

ChemMedChem. 2010 Aug 2;5(8):1324-34. doi: 10.1002/cmdc.201000133.

Abstract

Prion diseases are fatal neurodegenerative and infectious disorders for which effective pharmacological tools are not yet available. This unmet challenge and the recently proposed interplay between prion diseases and Alzheimer's have led to a more urgent demand for new antiprion agents. Herein, we report the identification of a novel bifunctional diketopiperazine (DKP) derivative 1 d, which exhibits activity in the low micromolar range against prion replication in ScGT1 cells, while showing low cytotoxicity. Supported by properly addressed molecular modeling studies, we hypothesized that a planar conformation is the major determinant for activity in this class of compounds. Moreover, studies aimed at assessing the mechanism-of-action at the molecular level showed that 1 d might interact directly with recombinant prion protein (recPrP) to prevent its conversion to the pathogenic misfolded prion protein (PrP(Sc))-like form. This investigation suggests that DKP based antiprion compounds can serve as a promising lead scaffold in developing new drugs to combat prion diseases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line
  • Diketopiperazines / chemistry*
  • Diketopiperazines / therapeutic use
  • Drug Evaluation, Preclinical
  • Humans
  • Models, Molecular
  • Prion Diseases / drug therapy
  • Prions / antagonists & inhibitors*
  • Prions / genetics
  • Prions / metabolism
  • Recombinant Proteins / antagonists & inhibitors
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / therapeutic use

Substances

  • Diketopiperazines
  • Prions
  • Recombinant Proteins
  • Small Molecule Libraries