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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. ReyEmail author
Original Paper
Part of the following topical collections:
  1. Metal Ions and Degenerative Diseases

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.

Keywords

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

Abbreviations

dMKHA

Ac-SKPKTNMKHA-NH2

HPCIH

Pyridine-2-carboxaldehyde isonicotinoyl hydrazone

HPCFur

Pyridine-2-carboxaldehyde 2-furoyl hydrazone

PrPC

Cellular prion protein

PrPSc

Scrapie prion protein

ROS

Reactive oxygen species

RP-HPLC

Reverse-phase high performance liquid chromatography

TFA

Trifluoroacetic acid

Notes

Acknowledgements

NAR, DSC, and BNE are grateful for the scientific Brazilian funding agencies FAPERJ (Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro, Brazil), CAPES (Coordenação de Aperfeiçoamento de Pessoal de Nível Superior, Brazil), and CNPq (Conselho Nacional de Desenvolvimento Científico e Tecnológico, Brazil) for the research fellowships and scholarships awarded. The financial support from the Hungarian Scientific Research Fund (NKFI-115480 and NKFI-128783) is appreciated. The research was supported by the EU and co-financed by the European Regional Development Fund under the project GINOP-2.3.2-15-2016-00008. The Hungarian co-authors also thank the UNKP-18-4 New National Excellence Program of the Ministry of Human Capacities. This research was also financed by the János Bolyai Research Scholarship of the Hungarian Academy of Sciences. The authors wish to thank Prof. Dr. Christian Griesinger, director of the NMR-based Structural Biology Department, for his support and fruitful discussions, and Kerstin Overkamp, from the same institution, for her experimental support in the ESI-MS measurements.

Supplementary material

775_2019_1700_MOESM1_ESM.pdf (686 kb)
Supplementary material 1 (PDF 686 kb)

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Copyright information

© Society for Biological Inorganic Chemistry (SBIC) 2019

Authors and Affiliations

  1. 1.Departamento de Química, Pontifícia Universidade Católica do Rio de JaneiroRio de JaneiroBrazil
  2. 2.Department of Inorganic and Analytical ChemistryUniversity of DebrecenDebrecenHungary
  3. 3.Department of Applied ChemistryUniversity of DebrecenDebrecenHungary
  4. 4.NMR-based Structural Biology, Max Planck Institute for Biophysical ChemistryGöttingenGermany

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