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Antimicrob. Agents Chemother. doi:10.1128/AAC.01112-08
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

A Variety of Anti-Prion Compounds Discovered through an in silico Screen Based on PrP^C Structure: A Correlation between Anti-Prion Activity and Binding Affinity

Center for Emerging Infectious Diseases, Gifu University, 1-1 Yanagido, Gifu 501-1194, Japan

^* To whom correspondence should be addressed. Email: kuwata{at}gifu-u.ac.jp.

	Abstract

Transmissible spongiform encephalopathies are associated with the conformational conversion of the prion protein (PrP) from the cellular form (PrP^C) to the scrapie form (PrP^Sc). This process could be disrupted by stabilizing the PrP^C conformation using a specific ligand named chemical chaperone.

To discover such compounds, we employed an in silico screen that was based on the NMR structure of PrP^C. In combination, we performed ex vivo screening using the Fukuoka-1 strain-infected neuronal mouse cell line at a compound concentration of 10 µM and surface plasmon resonance. Initially, we selected 590 compounds according to the calculated docked energy and finally discovered 24 efficient anti-prion compounds, whose chemical structures are quite diverse.

Surface plasmon resonance studies showed that the binding affinities of compounds to PrP^C roughly correlated with their anti-prion activities, indicating that identification of chemical chaperones that bind to the PrP^C structure and stabilize it is one of the efficient strategy for anti-prion drug discovery. However, some compounds possessed anti-prion activities with low affinities to PrP^C, indicating a mechanism involving additional modulation factors. We classified the compounds roughly into five categories: (i) binding and effective (BE), (ii) low binding and effective (LBE), (iii) binding and not effective (BNE), (iv) low binding and not effective (LBNE), and (v) acceleration (A).

In conclusion, we found a spectrum of compounds, many of which are able to modulate the pathogenic conversion reaction. The appropriate categorization of these diverse compounds would facilitate anti-prion drug discovery and help elucidate the pathogenic conversion mechanism.