Discovery of a class of diketopiperazines as antiprion compounds

Maria Laura Bolognesi, Hoang Ngoc Ai Tran, Matteo Staderini, Alessandra Monaco, Alberto López-Cobẽas, Salvatore Bongarzone, Xevi Biarnés, Pilar López-Alvarado, Nieves Cabezas, Maria Caramelli, Paolo Carloni, J. Carlos Menéndez, Giuseppe Legname

Research output: Indexed journal article Articlepeer-review

44 Citations (Scopus)

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 1d, 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 1d might interact directly with recombinant prion protein (recPrP) to prevent its conversion to the pathogenic misfolded prion protein (PrPSc)-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.

Original languageEnglish
Pages (from-to)1324-1334
Number of pages11
JournalChemMedChem
Volume5
Issue number8
DOIs
Publication statusPublished - 2 Aug 2010
Externally publishedYes

Keywords

  • Computational chemistry
  • Drug design
  • Fibrillation inhibitors
  • Prion diseases

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