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Multimodal small-molecule screening for human prion protein binders.

Andrew G Reidenbach1, Michael F Mesleh2, Dominick Casalena3

  • 1Chemical Biology and Therapeutics Science Program, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.

The Journal of Biological Chemistry
|July 30, 2020
PubMed
Summary
This summary is machine-generated.

Researchers sought small-molecule drugs to treat prion disease by targeting the prion protein (PrP). Despite extensive screening, no effective drug binders were found, indicating PrP is a challenging target.

Keywords:
19F NMRDNA-encoded libraryDSFPrPSTD NMRTROSY NMRbindersdifferential scanning fluorimetrydrug discoverydrug screeningfragment screeninghigh-throughput screening (HTS)in silico screeningneurodegenerative diseasenuclear magnetic resonance (NMR)prionprion diseasesmall molecule

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Area of Science:

  • Neuroscience
  • Biochemistry
  • Drug Discovery

Background:

  • Prion diseases are fatal neurodegenerative disorders caused by misfolded prion protein (PrP).
  • Currently, no effective therapeutic options exist for prion diseases.
  • Small-molecule PrP ligands could offer a therapeutic strategy by preventing protein misfolding or promoting degradation.

Purpose of the Study:

  • To discover validated small-molecule binders of the prion protein (PrP).
  • To identify potential therapeutic agents for prion diseases.

Main Methods:

  • Utilized diverse screening techniques: 19F-observed NMR, STD NMR, differential scanning fluorimetry (DSF), DNA-encoded library selection, and in silico screening.
  • Employed concentration-response assays to validate initial findings.

Main Results:

  • A single benzimidazole compound showed weak binding affinity (Kd > 1 mM) and could not be advanced.
  • The study observed an exceptionally low hit rate, suggesting PrP is a difficult target for small-molecule drug discovery.
  • No validated high-affinity small-molecule PrP binders were identified.

Conclusions:

  • Prion protein (PrP) presents a significant challenge for small-molecule binder discovery.
  • Alternative therapeutic strategies, potentially involving non-small-molecule modalities, may be necessary for treating prion diseases.