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, C. Kállay, Nicolás A. Rey

Research output: Contribution to journalArticle

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
JournalJournal of Biological Inorganic Chemistry
DOIs
Publication statusPublished - Jan 1 2019

Fingerprint

Copper
Metals
Oxidation
Prions
Hydrazones
Prion Diseases
PrPSc Proteins
Trace Elements
Neurodegenerative diseases
Histidine
Neurodegenerative Diseases
Methionine
Oxidation-Reduction
Oxidative stress
Oxidative Stress
Biomolecules
Pathology
Iron
Ions
Ligands

Keywords

  • Aroylhydrazones
  • Copper(II)
  • Human prion protein
  • Methionine oxidation
  • Oxidative stress

ASJC Scopus subject areas

  • Biochemistry
  • Inorganic Chemistry

Cite this

Impact of pyridine-2-carboxaldehyde-derived aroylhydrazones on the copper-catalyzed oxidation of the M112A PrP103–112 mutant fragment. / Cukierman, Daphne S.; Bodnár, Nikolett; Evangelista, Beatriz N.; Nagy, Lajos; Kállay, C.; Rey, Nicolás A.

In: Journal of Biological Inorganic Chemistry, 01.01.2019.

Research output: Contribution to journalArticle

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AU - Kállay, C.

AU - Rey, Nicolás A.

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