Antimalarial Drug Quinacrine Binds to C-Terminal Helix of Cellular Prion Protein

Vogtherr, Martin; Grimme, Susanne; Elshorst, Bettina; Jacobs, Doris M.; Fiebig, Klaus M.; Griesinger, Christian; Zahn, Ralph

doi:10.1021/jm034093h

Cited by 95 publications

(80 citation statements)

References 16 publications

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“…The IC 50 value obtained of 1.6 AE 0.4 μM is in good agreement with the K d values obtained by ITC, induced CD, and AUC, suggesting the most likely mode of action of Fe(III)-TMPyP in cells is inhibiting prion propagation by binding to the ground state of PrP C and preventing its conversion to PrP Sc . This contrasts with quinacrine, which is believed to concentrate in specific organelles (44) and where the cell curing is around 100,000-fold higher than the K d calculated by NMR (43). The increased cell potency of Fe(III)-TMPyP may be related to its tendency to locate near anionic lipids (46) or may suggest that not all PrP needs to be stabilized to cure prion-infected cells, allowing curing below the K d for the compound.…”

Section: Discussionmentioning

confidence: 88%

Pharmacological chaperone for the structured domain of human prion protein

Nicoll¹,

Trevitt

Tattum

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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In prion diseases, the misfolded protein aggregates are derived from cellular prion protein (PrP C ). Numerous ligands have been reported to bind to human PrP C (huPrP), but none to the structured region with the affinity required for a pharmacological chaperone. Using equilibrium dialysis, we screened molecules previously suggested to interact with PrP to discriminate between those which did not interact with PrP, behaved as nonspecific polyionic aggregates or formed a genuine interaction. Those that bind could potentially act as pharmacological chaperones. Here we report that a cationic tetrapyrrole [Fe(III)-TMPyP], which displays potent antiprion activity, binds to the structured region of huPrP. Using a battery of biophysical techniques, we demonstrate that Fe(III)-TMPyP forms a 1∶1 complex via the structured C terminus of huPrP with a K d of 4.5 ± 2 μM, which is in the range of its IC 50 for curing prion-infected cells of 1.6 ± 0.4 μM and the concentration required to inhibit protein-misfolding cyclic amplification. Therefore, this molecule tests the hypothesis that stabilization of huPrP C , as a principle, could be used in the treatment of human prion disease. The identification of a binding site with a defined 3D structure opens up the possibility of designing small molecules that stabilize huPrP and prevent its conversion into the disease-associated form.

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Section: Discussionmentioning

confidence: 88%

Pharmacological chaperone for the structured domain of human prion protein

Nicoll¹,

Trevitt

Tattum

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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“…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).…”

Section: Discussionmentioning

confidence: 99%

Quinacrine promotes replication and conformational mutation of chronic wasting disease prions

Bian

Kang

Telling

2014

Proc. Natl. Acad. Sci. U.S.A.

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Quinacrine's ability to reduce levels of pathogenic prion protein (PrP Sc ) in mouse cells infected with experimentally adapted prions led to several unsuccessful clinical studies in patients with prion diseases, a 10-y investment to understand its mechanism of action, and the production of related compounds with expectations of greater efficacy. We show here, in stark contrast to this reported inhibitory effect, that quinacrine enhances deer and elk PrP Sc accumulation and promotes propagation of prions causing chronic wasting disease (CWD), a fatal, transmissible, neurodegenerative disorder of cervids of uncertain zoonotic potential. Surprisingly, despite increased prion titers in quinacrine-treated cells, transmission of the resulting prions produced prolonged incubation times and altered PrP Sc deposition patterns in the brains of diseased transgenic mice. This unexpected outcome is consistent with quinacrine affecting the intrinsic properties of the CWD prion. Accordingly, quinacrine-treated CWD prions were comprised of an altered PrP Sc conformation. Our findings provide convincing evidence for drug-induced conformational mutation of prions without the prerequisite of generating drug-resistant variants of the original strain. More specifically, they show that a drug capable of restraining prions in one species/strain setting, and consequently used to treat human prion diseases, improves replicative ability in another and therefore force reconsideration of current strategies to screen antiprion compounds.prion therapeutics | prion enhancing drugs P rions are protein-based infectious agents that cause an increasing variety of fatal, infectious neurodegenerative disorders, frequently as epidemics. Variant Creutzfeldt-Jakob disease (CJD) resulting from bovine spongiform encephalopathy exemplifies prion zoonosis, and the continued, unpredictable emergence of additional epidemics in other species, particularly chronic wasting disease (CWD) in deer, elk, and moose, raises additional concerns. Its unprecedented contagious spread, widening host range, and conflicting evidence surrounding its zoonotic potential place CWD at the forefront of public health concerns. Although the notion, that prion replication occurs by corruption of host-encoded cellular prion protein (PrP C ) by abnormally conformed PrP Sc , is now widely accepted, the details of this mechanism remain enigmatic.Except under certain experimental conditions, treatments capable of arresting or of effectively modifying the course of disease do not exist for prion disorders. Compounds targeting prevention of PrP misfolding have been aggressively pursued as therapeutics. Cells chronically infected with rodent prions are used as a means either to screen compounds inhibiting PrP Sc accumulation (1-5) or to confirm the proposed antiprion effects of compounds discovered by other means (6, 7). Such strategies rest on the assumption that compounds with efficacy against experimentally adapted rodent prions will be effective against naturally occurring prions, in ...

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“…In the first set of entries (1-15) the synthesized 9-chloroacridines were coupled with commercially available sidechain 9{1,9}, while in the second set of entries (16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31), the commercially available 9-chloroacridine heterocycle 7{4,6} of quinacrine was coupled with the set of synthesized diamines. Yields and purities of the coupled products were highly variable.…”

Section: Proof-of-concept Librarymentioning

confidence: 99%

“…The latter two items were conveniently added in parallel via the Bohdan Resin Dispenser accessory. The block was simultaneously heated to 100 °C and agitated at 600 RPM using the Bohdan MiniBlock High Capacity Shaking and Washing Station for 2 h. RP-LCMS usually showed quantitative conversion to the 9-phenoxyacridine chemset (17). Next, diamines (9) were added (125 μL DMSO stock, 4 eq.)…”

Section: General Procedures For Parallel Reductive Amination and Nosylmentioning

confidence: 99%

“…Next, diamines (9) were added (125 μL DMSO stock, 4 eq.) and the blocks heated again to 100 °C at 600 RPM for 4 h. RP-LCMS analysis showed the presence of 9-aminoacridine product (10), as well as varying amounts of 9-acridone (17). Unreacted primary amine was scavenged by treatment with methyl isocyanate polystyrene resin (NovaBiochem, 1.40 mmol/ g loading, 8 eq.)…”

Section: General Procedures For Parallel Reductive Amination and Nosylmentioning

confidence: 99%

See 1 more Smart Citation

Parallel synthesis of 9-aminoacridines and their evaluation against chloroquine-resistant Plasmodium falciparum

Anderson

Sherrill

Madrid

et al. 2006

Bioorganic & Medicinal Chemistry

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A parallel synthetic strategy to the 9-aminoacridine scaffold of the classical anti-malarial drug quinacrine (2) is presented. The method features a new route to 9-chloroacridines that utilizes triflates of salicylic acid derivatives, which are commercially available in a variety of substitution patterns. The route allows ready variation of the two diversity elements present in this class of molecules: the tricyclic aromatic heterocyclic core, and the disubstituted diamine sidechain. In this study, a library of 175 compounds was designed, although only 93 of the final products had purities acceptable for screening. Impurity was generally due to incomplete removal of 9-acridones (18), a degradation product of the 9-chloroacridine synthetic intermediates. The library was screened against two strains of Plasmodium falciparum, including a model of the drug-resistant parasite, and six novel compounds were found to have IC 50 values in the low nanomolar range.

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Antimalarial Drug Quinacrine Binds to C-Terminal Helix of Cellular Prion Protein

Cited by 95 publications

References 16 publications

Pharmacological chaperone for the structured domain of human prion protein

Pharmacological chaperone for the structured domain of human prion protein

Quinacrine promotes replication and conformational mutation of chronic wasting disease prions

Parallel synthesis of 9-aminoacridines and their evaluation against chloroquine-resistant Plasmodium falciparum

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