Multimodal small-molecule screening for human prion protein binders.
J Biol Chem
; 295(39): 13516-13531, 2020 09 25.
Article
em En
| MEDLINE
| ID: mdl-32723867
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 (Kd > 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.
Palavras-chave
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
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Benzimidazóis
/
Doenças Priônicas
/
Bibliotecas de Moléculas Pequenas
/
Proteínas Priônicas
Tipo de estudo:
Diagnostic_studies
/
Screening_studies
Idioma:
En
Revista:
J Biol Chem
Ano de publicação:
2020
Tipo de documento:
Article
País de afiliação:
Estados Unidos