Multimodal small-molecule screening for human prion protein binders.

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

SUBMITTER: Reidenbach AG 

PROVIDER: S-EPMC7521658 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature