Inhibitory effects of fluorinated benzenesulfonamides on insulin fibrillation

Saeid Hadi Alijanvand, Lucy Kate Ladefoged, Asta Zubrienė, Andrius Sakalauskas, Gunna Christiansen, Virginija Dudutiene, Birgit Schiøtt, Daumantas Matulis, Vytautas Smirnovas, Daniel E Otzen*

*Corresponding author for this work

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

Abstract

Amyloid fibrils are protein aggregates formed by protein assembly through cross β structures. Inhibition of amyloid fibril formation may contribute to therapy against amyloid-related disorders like Parkinson's, Alzheimer's, and type 2 diabetes. Here we report that several fluorinated sulfonamide compounds, previously shown to inhibit human carbonic anhydrase, also inhibit the fibrillation of different proteins. Using a range of spectroscopic, microscopic and chromatographic techniques, we found that the two fluorinated sulfonamide compounds completely inhibit insulin fibrillation over a period of 16 h and moderately suppress α-synuclein and Aβ fibrillation. In addition, these compounds decreased cell toxicity of insulin incubated under fibrillation-inducing conditions. We ascribe these effects to their ability to maintain insulin in the native monomeric state. Molecular dynamic simulations suggest that these compounds inhibit insulin self-association by interacting with residues at the dimer interface. This highlights the general anti-aggregative properties of aromatic sulfonamides and suggests that sulfonamide compounds which inhibit carbonic anhydrase activity may have potential as therapeutic agents against amyloid-related disorders.

Original languageEnglish
JournalInternational Journal of Biological Macromolecules
Volume227
Pages (from-to)590-600
Number of pages11
ISSN0141-8130
DOIs
Publication statusPublished - Feb 2023

Keywords

  • Carbonic anhydrase inhibitors
  • Insulin
  • Protein fibrillation inhibitors
  • Sulfonamide compounds
  • Carbonic Anhydrase Inhibitors/pharmacology
  • Sulfonamides/pharmacology
  • Amyloid/chemistry
  • Carbonic Anhydrases
  • Humans
  • Diabetes Mellitus, Type 2
  • Insulin/chemistry

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