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Multimodal small-molecule screening for human prion protein binders

Auld, Douglas, Casalena, Dominick and Wright, Kirk (2020) Multimodal small-molecule screening for human prion protein binders. Journal of Biological Chemistry, 295 (39). ISSN 0021-92581083-351X


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 stabilizing the native protein 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) nuclear magnetic resonance (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. Additional orthogonal approaches to PrP binder discovery should be pursued in parallel with non-small-molecule modalities

Item Type: Article
Date Deposited: 22 Oct 2020 00:45
Last Modified: 22 Oct 2020 00:45


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