Novel noscapine derivatives stabilize the native state of insulin against fibrillation

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  • Saeid Hadi Alijanvand, University of Tehran
  • ,
  • Mikkel Hovden Christensen
  • Gunna Christiansen
  • Kosar Babanezhad Harikandei, Department of Phytochemistry, Medicinal Plants and Drugs Research Institute, Shahid Beheshti University, Evin, Tehran, Iran.
  • ,
  • Peyman Salehi, Department of Phytochemistry, Medicinal Plants and Drugs Research Institute, Shahid Beheshti University, Evin, Tehran, Iran.
  • ,
  • Birgit Schiøtt
  • Ali Akbar Moosavi-Movahedi, Institute of Biochemistry and Biophysics (IBB), University of Tehran, Tehran, Iran. Electronic address: moosavi@ut.ac.ir.
  • ,
  • Daniel E Otzen

Protein aggregation to form amyloid is associated with many human diseases, increasing the need to develop inhibitors of this process. Here we evaluate the ability of derivatives of the small organic compound noscapine, derived from the opium poppy, to inhibit fibrillation of the model protein insulin. We combined biophysical methods to assess insulin stability and aggregation with computational docking and cell viability studies to identify the most potent derivatives. The best aggregation inhibitor (a phenyl derivative of N-nornoscapine) also demonstrated the highest ability to stabilize native insulin against thermal denaturation. This compound maintained insulin largely in the monomeric and natively folded state under fibrillation conditions and also decreased insulin aggregate toxicity against human neuroblastoma SH-SY5Y cells. The inhibitory effects were specific for insulin fibrillation, as the noscapine compounds did not inhibit fibrillation of other proteins such as α-synuclein, Aβ, and FapC. Our data demonstrate that compounds which stabilize the folded native state of a protein can not only inhibit fibrillation but also decrease the toxicity of the mature fibrillar aggregates of insulin protein.

OriginalsprogEngelsk
TidsskriftInternational Journal of Biological Macromolecules
Vol/bind147
Sider (fra-til)98-108
Antal sider11
ISSN0141-8130
DOI
StatusUdgivet - mar. 2020

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