SAR by kinetics for drug discovery in protein misfolding diseases

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

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.

Detaljer

Författare
  • Sean Chia
  • Johnny Habchi
  • Thomas C.T. Michaels
  • Samuel I.A. Cohen
  • Sara Linse
  • Christopher M. Dobson
  • Tuomas P.J. Knowles
  • Michele Vendruscolo
Enheter & grupper
Externa organisationer
  • University of Cambridge
  • Harvard University
Forskningsområden

Ämnesklassifikation (UKÄ) – OBLIGATORISK

  • Biokemi och molekylärbiologi

Nyckelord

Originalspråkengelska
Sidor (från-till)10245-10250
Antal sidor6
TidskriftProceedings of the National Academy of Sciences of the United States of America
Volym115
Utgivningsnummer41
StatusPublished - 2018
PublikationskategoriForskning
Peer review utfördJa