Quinacrine blocks PrP (106–126)‐formed channels

Abstract

We investigated the action of the acridine derivative, quinacrine (QC), which has been shown to act as a noncompetitive channel inhibitor. The main effects of QC are voltage- and concentration-dependent changes in the kinetics of the prion protein fragment (PrP[106-126])-formed cation channels. The current-voltage relationships show that the maximal current (I) was not affected whereas the physiologically important mean current (I') was reduced as a result of changes in channel kinetics. These findings suggest that QC acts on the open state of the channels. The half-inhibitory concentration (IC50) for the dose-dependent effects of [QC]cis on the kinetic parameters of the PrP(106-126)-formed cation channel shows a reduction in the ratios Po(QC)/Po, Fo(QC)/Fo, and To(QC)/To, whereas Tc(QC)/Tc increases. Of these ratios, Po(QC)/Po was more sensitive than the others. The corresponding IC50 for these ratios were 51, 94, 86, and 250 microM QC, respectively. The QC-induced changes in the kinetic parameters were more apparent at positive voltages. IC50 values for Po were 95, 75, and 51 microM at +20, +80, and +140 mV, respectively. The fact that QC induced changes in the kinetics of this channel, although the conductance of the channel remained unchanged, indicates that QC may bind at the mouth of the channel via a mechanism known as fast channel block. The QC-induced changes in the kinetic parameters of this channel suggest that they are pathophysiologically significant because these channels could be the mechanisms by which amyloids induce membrane damage in vivo.

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).…”

Review: PrP 106‐126 – 25 years after

“…, the possible interactions with neuronal membranes of the oligomers independent from the sequences can be traced to three possible mechanisms: i) specific interaction with the protein entity; ii) unspecific interaction with membranes; iii) formation of membrane pores. Chemicophysical analysis demonstrates the formation of PrP106‐126 oligomers that can disrupt membranes and form channels . In AD, soluble Aβ oligomers were initially considered the precursors of amyloid fibres and although their toxicity was demonstrated , only later were they considered central in AD pathogenesis .…”

Inhibitors of Brain Phospholipase A2Activity: Their Neuropharmacological Effects and Therapeutic Importance for the Treatment of Neurologic Disorders

“…The molecular mechanism involved in the inhibition of PrP sc formation by quinacrine remains unknown. However, it has been suggested that quinacrine blocks PrP106-126 formed channels (Farrelly et al, 2003). NMR spectroscopic studies indicate that the PLA 2 inhibitor, quinacrine, binds to human prion protein at the Tyr-225, Tyr-226, and Gln-227 residues of helix ␣3 (Vogtherr et al, 2003).…”