Chelating Compound, Chrysoidine, Is More Effective in Both Antiprion Activity and Brain Endothelial Permeability Than Quinacrine

Abstract

1. As an extension of our previous study of quinacrine and its derivatives, chelating chemicals were screened to obtain more effective, better brain-permeable antiprion compounds using either prion-infected neuroblastoma cells or brain capillary endothelial cells.2. Eleven chemicals were found to have antiprion activity. Most of them shared a common structure consisting of benzene or naphthalene at either end of an azo bond. Structure-activity data suggest that chelating activity is not necessary but might contribute to the antiprion action.3. Chrysoidine, a representative compound found here, was about 27 times more effective in the antiprion activity and five times more efficiently permeable through the brain capillary endothelial cells than quinacrine was.4. These chemicals might be useful as compounds for development of therapeutics for prion diseases.

Quinacrine promotes replication and conformational mutation of chronic wasting disease prions

“…First, the effects of "antiprion" compounds are clearly species/strain-dependent, in that drugs found to restrain prions in one situation may improve replicative ability in another. Based on initial reports of quinacrine's effects on mouse prion propagation in cell culture, a plethora of studies were designed to discern the mechanism of its presumed antiprion effects (19,20,(29)(30)(31)(38)(39)(40)(41)(42)(43)(44)(45), to assess its pharmacokinetics (21,36,42,46) and to derive similar compounds with improved antiprion efficacy (18,20,(47)(48)(49)(50)(51)(52)(53)(54)(55)(56)(57)(58)(59). These studies continue to this day, despite multiple failed clinical studies in patients with human prion diseases (10)(11)(12)(13)(14)(15).…”

Insights from Therapeutic Studies for PrP Prion Disease

“…Among these models, prion-infected cell models have been the most frequently used since Congo red and polyanionic glycans were found to possess antiprion activity (Caughey and Race 1992;Caughey and Raymond 1993). In fact, our research group has identified dozens of antiprion compounds, including quinacrine and compB, using prion-infected cell models (Doh-ura et al 2000(Doh-ura et al , 2007bIshikawa et al 2004Ishikawa et al , 2006Murakami-Kubo et al 2004;Kawatake et al 2006;Kawasaki et al 2007;Nguyen et al 2008Nguyen et al , 2011Hamanaka et al 2011Hamanaka et al , 2015Teruya and Doh-ura 2013;Nishizawa et al 2014). However, these cell models are not fully compatible with in vivo prion-infected neuronal cells.…”

Reorganizing Metals: the Use of Chelating Compounds as Potential Therapies for Metal-Related Neurodegenerative Disease

“…Chrysoidine is a chelating agent with antiprion activity and an ability to easily cross the BBB. However, there is as yet no investigation into the drug's effect on human patients, and has been (inconclusively) associated with cancer [108]. Quinacrine Fig.…”

“…The structure of quinacrine would suggest that it should act as a chelating agent; however it is likely that the drug has a different mode of action that doesn't rely exclusively on its chelating ability. Administration of the drug does not alter the amounts of PrP C or modify PrP Sc , so the mechanism of the drug is still unknown [108]. Interestingly, although clioquinol and related compounds are effective in assisting in the reduction of A in AD, it was not shown to have an effect against PrP Sc accumulation [109].…”