Impact of pyridine-2-carboxaldehyde-derived aroylhydrazones on the copper-catalyzed oxidation of the M112A PrP103–112 mutant fragment

Daphne S. Cukierman, Nikolett Bodnár, Beatriz N. Evangelista, Lajos Nagy, Csilla Kállay, Nicolás A. Rey

Research output: Article

1 Citation (Scopus)

Abstract

Misfolded prion protein (PrPSc) is known for its role in fatal neurodegenerative conditions, such as Creutzfeldt–Jakob disease. PrP fragments and their mutants represent important tools in the investigation of the neurotoxic mechanisms and in the evaluation of new compounds that can interfere with the processes involved in neuronal death. Metal-catalyzed oxidation of PrP has been implicated as a trigger for the conformational changes in protein structure, which, in turn, lead to misfolding. Targeting redox-active biometals copper and iron is relevant in the context of protection against the oxidation of biomolecules and the generation of oxidative stress, observed in several conditions and considered an event that might promote sporadic prion diseases as well as other neurodegenerative disorders. In this context, ortho-pyridine aroylhydrazones are of interest, as they can act as moderate tridentate ligands towards divalent metal ions such as copper(II). In the present work, we explore the potentiality of this chemical class as peptide protecting agents against the deleterious metal-catalyzed oxidation in the M112A mutant fragment of human PrP, which mimics relevant structural features that may play an important role in the neurotoxicity observed in prion pathologies. The compounds inhere studied, especially HPCFur, showed an improved stability in aqueous solution compared to our patented lead hydrazone INHHQ, displaying a very interesting protective effect toward the oxidation of methionine and histidine, processes that are related to both physiological and pathological aging.

Original languageEnglish
Pages (from-to)1231-1244
Number of pages14
JournalJournal of Biological Inorganic Chemistry
Volume24
Issue number8
DOIs
Publication statusPublished - dec. 1 2019

ASJC Scopus subject areas

  • Biochemistry
  • Inorganic Chemistry

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