SAR by kinetics for drug discovery in protein misfolding diseases

Sean Chia, Johnny Habchi, Thomas C.T. Michaels, Samuel I.A. Cohen, Sara Linse, Christopher M. Dobson, Tuomas P.J. Knowles, Michele Vendruscolo

Research output: Contribution to journalArticlepeer-review

28 Citations (SciVal)

Abstract

To develop effective therapeutic strategies for protein misfolding diseases, a promising route is to identify compounds that inhibit the formation of protein oligomers. To achieve this goal, we report a structure.activity relationship (SAR) approach based on chemical kinetics to estimate quantitatively how small molecules modify the reactive flux toward oligomers. We use this estimate to derive chemical rules in the case of the amyloid beta peptide (Aβ), which we then exploit to optimize starting compounds to curtail Aâ oligomer formation. We demonstrate this approach by converting an inactive rhodanine compound into an effective inhibitor of Aβ oligomer formation by generating chemical derivatives in a systematic manner. These results provide an initial demonstration of the potential of drug discovery strategies based on targeting directly the production of protein oligomers.

Original languageEnglish
Pages (from-to)10245-10250
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number41
DOIs
Publication statusPublished - 2018

Subject classification (UKÄ)

  • Biochemistry and Molecular Biology

Keywords

  • Alzheimer's disease
  • Amyloid beta peptide
  • Chemical kinetics
  • Protein aggregation
  • Protein misfolding

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