Characterizing antiprion compounds based on their binding properties to prion proteins: Implications as medical chaperones. (19th November 2012)

• Record Type: Journal Article
• Authors: Kamatari, Yuji O.; Hayano, Yosuke; Yamaguchi, Kei‐ichi; Hosokawa‐Muto, Junji; Kuwata, Kazuo
• Is Part Of: Protein science. Volume 22:Number 1(2013:Jan.)
• Page Start: 22
• Page End: 34
• Publication Date: 2012-11-19
• Subjects: Proteins -- Periodicals; 572.6
• DOI: 10.1002/pro.2180
• Languages: English
• ISSNs: 0961-8368

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>Abstract</title> <p>A variety of antiprion compounds have been reported that are effective in <italic>ex vivo</italic> and <italic>in vivo</italic> treatment experiments. However, the molecular mechanisms for most of these compounds remain unknown. Here we classified antiprion mechanisms into four categories: I, specific conformational stabilization; II, nonspecific stabilization; III, aggregation; and IV, interaction with molecules other than PrP<sup>C</sup>. To characterize antiprion compounds based on this classification, we determined their binding affinities to PrP<sup>C</sup> using surface plasmon resonance and their binding sites on PrP<sup>C</sup> using NMR spectroscopy. GN8 and GJP49 bound specifically to the hot spot in PrP<sup>C</sup>, and acted as "medical chaperones" to stabilize the native conformation. Thus, mechanisms I was predominant. In contrast, quinacrine and epigallocathechin bound to PrP<sup>C</sup> rather nonspecifically; these may stabilize the PrP<sup>C</sup> conformation nonspecifically including the interference with the intermolecular interaction following mechanism II. Congo red and pentosan polysulfate bound to PrP<sup>C</sup> and caused aggregation and precipitation of PrP<sup>C</sup>, thus reducing the effective concentration of prion protein. Thus, mechanism III was appropriate. Finally, CP‐60, an edarabone derivative, did not bind to PrP<sup>C</sup>. Thus these were classified into mechanism IV. However, their antiprion activities were not confirmed in the GT + FK system, whose details remain to be elucidated. This proposed antiprion mechanisms of diverse antiprion compounds could help to elucidate their antiprion activities and facilitate effective antiprion drug discovery.</p> </abstract>