Multimodal small-molecule screening for human prion protein binders

J Biol Chem. 2020 Sep 25;295(39):13516-13531. doi: 10.1074/jbc.RA120.014905. Epub 2020 Jul 28.

Abstract

Prion disease is a rapidly progressive neurodegenerative disorder caused by misfolding and aggregation of the prion protein (PrP), and there are currently no therapeutic options. PrP ligands could theoretically antagonize prion formation by protecting the native protein from misfolding or by targeting it for degradation, but no validated small-molecule binders have been discovered to date. We deployed a variety of screening methods in an effort to discover binders of PrP, including 19F-observed and saturation transfer difference (STD) NMR spectroscopy, differential scanning fluorimetry (DSF), DNA-encoded library selection, and in silico screening. A single benzimidazole compound was confirmed in concentration-response, but affinity was very weak (K d > 1 mm), and it could not be advanced further. The exceptionally low hit rate observed here suggests that PrP is a difficult target for small-molecule binders. Whereas orthogonal binder discovery methods could yield high-affinity compounds, non-small-molecule modalities may offer independent paths forward against prion disease.

Keywords: 19F NMR; DNA-encoded library; DSF; PrP; STD NMR; TROSY NMR; binders; differential scanning fluorimetry; drug discovery; drug screening; fragment screening; high-throughput screening (HTS); in silico screening; neurodegenerative disease; nuclear magnetic resonance (NMR); prion; prion disease; small molecule.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Benzimidazoles / chemistry
  • Benzimidazoles / pharmacology*
  • Drug Discovery
  • Drug Evaluation, Preclinical
  • Humans
  • Magnetic Resonance Spectroscopy
  • Prion Diseases / drug therapy*
  • Prion Diseases / metabolism
  • Prion Proteins / antagonists & inhibitors*
  • Prion Proteins / metabolism
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology*

Substances

  • Benzimidazoles
  • Prion Proteins
  • Small Molecule Libraries
  • benzimidazole

Associated data

  • PDB/1HJM
  • PDB/4MA7