Bifunctional compounds for controlling metal-mediated aggregation of the Aβ 42 peptide

Anuj K. Sharma, Stephanie T. Pavlova, Jaekwang Kim, Darren Finkelstein, Nicholas J. Hawco, Nigam P. Rath, Jungsu Kim, Liviu M. Mirica

Research output: Contribution to journalArticle

134 Citations (Scopus)

Abstract

Abnormal interactions of Cu and Zn ions with the amyloid β (Aβ) peptide are proposed to play an important role in the pathogenesis of Alzheimers disease (AD). Disruption of these metal-peptide interactions using chemical agents holds considerable promise as a therapeutic strategy to combat this incurable disease. Reported herein are two bifunctional compounds (BFCs) L1 and L2 that contain both amyloid-binding and metal-chelating molecular motifs. Both L1 and L2 exhibit high stability constants for Cu 2+ and Zn 2+ and thus are good chelators for these metal ions. In addition, L1 and L2 show strong affinity toward Aβ species. Both compounds are efficient inhibitors of the metal-mediated aggregation of the Aβ 42 peptide and promote disaggregation of amyloid fibrils, as observed by ThT fluorescence, native gel electrophoresis/Western blotting, and transmission electron microscopy (TEM). Interestingly, the formation of soluble Aβ 42 oligomers in the presence of metal ions and BFCs leads to an increased cellular toxicity. These results suggest that for the Aβ 42 peptide-in contrast to the Aβ 40 peptide-the previously employed strategy of inhibiting Aβ aggregation and promoting amyloid fibril dissagregation may not be optimal for the development of potential AD therapeutics, due to formation of neurotoxic soluble Aβ 42 oligomers.

Original languageEnglish (US)
Pages (from-to)6625-6636
Number of pages12
JournalJournal of the American Chemical Society
Volume134
Issue number15
DOIs
StatePublished - Apr 18 2012
Externally publishedYes

Fingerprint

Peptides
Agglomeration
Amyloid
Metals
Ions
Oligomers
Metal ions
Alzheimer Disease
Lead compounds
Corrosion inhibitors
Chelating Agents
Chelation
Electrophoresis
Transmission Electron Microscopy
Toxicity
Gels
Fluorescence
Western Blotting
Transmission electron microscopy
Therapeutics

ASJC Scopus subject areas

  • Chemistry(all)
  • Catalysis
  • Biochemistry
  • Colloid and Surface Chemistry

Cite this

Sharma, A. K., Pavlova, S. T., Kim, J., Finkelstein, D., Hawco, N. J., Rath, N. P., ... Mirica, L. M. (2012). Bifunctional compounds for controlling metal-mediated aggregation of the Aβ 42 peptide. Journal of the American Chemical Society, 134(15), 6625-6636. https://doi.org/10.1021/ja210588m

Bifunctional compounds for controlling metal-mediated aggregation of the Aβ 42 peptide. / Sharma, Anuj K.; Pavlova, Stephanie T.; Kim, Jaekwang; Finkelstein, Darren; Hawco, Nicholas J.; Rath, Nigam P.; Kim, Jungsu; Mirica, Liviu M.

In: Journal of the American Chemical Society, Vol. 134, No. 15, 18.04.2012, p. 6625-6636.

Research output: Contribution to journalArticle

Sharma, AK, Pavlova, ST, Kim, J, Finkelstein, D, Hawco, NJ, Rath, NP, Kim, J & Mirica, LM 2012, 'Bifunctional compounds for controlling metal-mediated aggregation of the Aβ 42 peptide', Journal of the American Chemical Society, vol. 134, no. 15, pp. 6625-6636. https://doi.org/10.1021/ja210588m
Sharma, Anuj K. ; Pavlova, Stephanie T. ; Kim, Jaekwang ; Finkelstein, Darren ; Hawco, Nicholas J. ; Rath, Nigam P. ; Kim, Jungsu ; Mirica, Liviu M. / Bifunctional compounds for controlling metal-mediated aggregation of the Aβ 42 peptide. In: Journal of the American Chemical Society. 2012 ; Vol. 134, No. 15. pp. 6625-6636.
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