Inhibition of aggregation of amyloid-β through covalent modification with benzylpenicillin; potential relevance to Alzheimer’s disease

Research output: Contribution to journalArticlepeer-review

  • External authors:
  • Izzeddin Alsalahat
  • Mutasem Taha
  • Nigel Hodson

Abstract

The pathogenesis of Alzheimer’s disease (AD) is correlated with the misfolding and aggregation of amyloid-beta
protein (Aβ). Here we report that the antibiotic benzylpenicillin (BP) can specifically bind to Aβ, modulate the
process of aggregation and supress its cytotoxic effect, initially via a reversible binding interaction, followed by
covalent bonding between specific functional groups (nucleophiles) within the Aβ peptide and the beta-lactam
ring. Mass spectrometry and computational docking supported covalent modification of Aβ by BP. BP was found
to inhibit aggregation of Aβ as revealed by the Thioflavin T (ThT) fluorescence assay and atomic force microscopy (AFM). In addition, BP treatment was found to have a cytoprotective activity against Aβ-induced cell
cytotoxicity as shown by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) cell toxicity
assay. The specific interaction of BP with Aβ suggests the possibility of structure-based drug design, leading to the
identification of new drug candidates against AD. Moreover, good pharmacokinetics of beta-lactam antibiotics
and safety on long-time use make them valuable candidates for drug repurposing towards neurological disorders
such as AD.

Bibliographical metadata

Original languageEnglish
Article number100943
JournalBiochemistry and Biophysics Reports
Volume26
Early online date15 Mar 2021
DOIs
Publication statusPublished - 1 Jul 2021