Stoichiometry and conditional stability constants of Cu(II) or Zn(II) clioquinol complexes; implications for Alzheimer's and Huntington's disease therapy

Ferrada, Evandro; Arancibia, Veróníca; Loeb, Bárbara; Norambuena, Ester; Olea‐Azar, Claudio; Huidobro‐Toro, J. Pablo

doi:10.1016/j.neuro.2007.02.004

Cited by 72 publications

(62 citation statements)

References 20 publications

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“…We included Zn because it is the most abundant physiological transition metal ion and therefore Cu's most likely competitor. The experimentally determined K f values for 8HQ and CQ complexes were in good agreement with those determined by Ferrada et al (51), who used conditions relatable to ours (see Table S1 in the supplemental material). By using these constants and the actual input concentrations of Cu ions and ligand, we were able to project the mole fractions of free ligands (L) and both metal complexes, ML and ML 2 (see Fig.…”

Section: Resultssupporting

confidence: 89%

8-Hydroxyquinolines Are Boosting Agents of Copper-Related Toxicity in Mycobacterium tuberculosis

Shah

Dalecki

Malalasekera

et al. 2016

Antimicrob Agents Chemother

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c Copper (Cu) ions are likely the most important immunological metal-related toxin utilized in controlling bacterial infections. Impairment of bacterial Cu resistance reduces viability within the host. Thus, pharmacological enhancement of Cu-mediated antibacterial toxicity may lead to novel strategies in drug discovery and development. Screening for Cu toxicity-enhancing antibacterial molecules identified 8-hydroxyquinoline (8HQ) to be a potent Cu-dependent bactericidal inhibitor of Mycobacterium tuberculosis. The MIC of 8HQ in the presence of Cu was 0.16 M for replicating and nonreplicating M. tuberculosis cells. We found 8HQ's activity to be dependent on the presence of extracellular Cu and to be related to an increase in cell-associated labile Cu ions. Both findings are consistent with 8HQ acting as a Cu ionophore. Accordingly, we identified the 1:1 complex of 8HQ and Cu to be its active form, with Zn, Fe, or Mn neither enhancing nor reducing its Cu-specific action. This is remarkable, considering that the respective metal complexes have nearly identical structures and geometries. Finally, we found 8HQ to kill M. tuberculosis selectively within infected primary macrophages. Given the stark Cu-dependent nature of 8HQ activity, this is the first piece of evidence that Cu ions within macrophages may bestow antibacterial properties to a Cu-dependent inhibitor of M. tuberculosis. In conclusion, our findings highlight the metal-binding ability of the 8-hydroxyquinoline scaffold to be a potential focus for future medicinal chemistry and highlight the potential of innate immunity-inspired screening platforms to reveal molecules with novel modes of action against M. tuberculosis.

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Section: Resultssupporting

confidence: 89%

8-Hydroxyquinolines Are Boosting Agents of Copper-Related Toxicity in Mycobacterium tuberculosis

Shah

Dalecki

Malalasekera

et al. 2016

Antimicrob Agents Chemother

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“…It was accordingly reported that clioquinol can prevent the inhibition by neurotoxic Cu 2+ of the ATP-gated currents evoked through the P2X 4 receptor. This was interpreted as an involvement of P2X 4 receptors in the neurotoxic effects exerted by metals in HD [42].…”

Section: Ischaemiamentioning

confidence: 97%

Membrane compartments and purinergic signalling: P2X receptors in neurodegenerative and neuroinflammatory events

et al. 2008

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ATP is a potent signalling molecule abundantly present in the nervous system, where it exerts physiological actions ranging from short‐term responses such as neurotransmission, neuromodulation and glial communication, to long‐term effects such as trophic actions. The fast signalling targets of extracellular ATP are represented by the ionotropic P2X receptors, which are broadly and abundantly expressed in neurons and glia in the whole central and peripheral nervous systems. Because massive extracellular release of ATP often occurs by lytic and non‐lytic mechanisms, especially after stressful events and pathological conditions, purinergic signalling is correlated to and involved in the aetiopathology and/or progression of many neurodegenerative diseases. In this minireview, we highlight the contribution of the subclass of ionotropic P2X receptors to several diseases of the human nervous system, such as neurodegenerative disorders and immune‐mediated neuroinflammatory dysfunctions including ischaemia, Parkinson’s, Alzheimer’s and Huntington’s diseases, amyotrophic lateral sclerosis and multiple sclerosis. The role of P2X receptors as novel and effective targets for the genetic/pharmacological manipulation of purinergic mechanisms in several neuropathological conditions is now well established. Nevertheless, any successful therapeutic intervention against these diseases cannot be restricted to P2X receptors, but should take into consideration the whole and multipart ATP signalling machinery.

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“…We used copper, iron, and zinc, all of which are known to bind CQ (27). On their own, none of these metals affected Aβ toxicity (Fig.…”

Section: Screen For Compounds That Rescue Aβ Toxicity In Yeastmentioning

confidence: 99%

Clioquinol promotes the degradation of metal-dependent amyloid-β (Aβ) oligomers to restore endocytosis and ameliorate Aβ toxicity

Matlack

Tardiff

Narayan

et al. 2014

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

155

141

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Alzheimer's disease (AD) is a common, progressive neurodegenerative disorder without effective disease-modifying therapies. The accumulation of amyloid-β peptide (Aβ) is associated with AD. However, identifying new compounds that antagonize the underlying cellular pathologies caused by Aβ has been hindered by a lack of cellular models amenable to high-throughput chemical screening. To address this gap, we use a robust and scalable yeast model of Aβ toxicity where the Aβ peptide transits through the secretory and endocytic compartments as it does in neurons. The pathogenic Aβ 1-42 peptide forms more oligomers and is more toxic than Aβ 1-40 and genome-wide genetic screens identified genes that are known risk factors for AD. Here, we report an unbiased screen of ∼140,000 compounds for rescue of Aβ toxicity. Of ∼30 hits, several were 8-hydroxyquinolines (8-OHQs). Clioquinol (CQ), an 8-OHQ previously reported to reduce Aβ burden, restore metal homeostasis, and improve cognition in mouse AD models, was also effective and rescued the toxicity of Aβ secreted from glutamatergic neurons in Caenorhabditis elegans. In yeast, CQ dramatically reduced Aβ peptide levels in a copper-dependent manner by increasing degradation, ultimately restoring endocytic function. This mirrored its effects on copper-dependent oligomer formation in vitro, which was also reversed by CQ. This unbiased screen indicates that copper-dependent Aβ oligomer formation contributes to Aβ toxicity within the secretory/endosomal pathways where it can be targeted with selective metal binding compounds. Establishing the ability of the Aβ yeast model to identify disease-relevant compounds supports its further exploitation as a validated early discovery platform.phenotypic small-molecule screen | metal chelation A lzheimer's disease (AD) is a common and devastating neurodegenerative disorder that is projected to increase in frequency as our population ages. The lack of disease-modifying therapies requires new approaches to address the underlying mechanisms of cellular dysfunction and identify potential therapeutics.The amyloid-β peptide (Aβ) plays a major role in AD and ultimately leads to neuronal death and cognitive impairment (1). Aβ peptides of ∼40 aa are generated by the successive cleavage of the amyloid precursor protein (APP) by β-and γ-secretases. Mutations in APP or γ-secretase cause familial AD and bias APP cleavage toward a 42-aa Aβ peptide that predominates in Aβ plaques, is more aggregation prone, and is toxic to neurons (2, 3). Although Aβ plaques are a common, conspicuous feature of pathology in diseased brains, increasing evidence suggests that small oligomers of Aβ are the most toxic species (4, 5).

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Stoichiometry and conditional stability constants of Cu(II) or Zn(II) clioquinol complexes; implications for Alzheimer's and Huntington's disease therapy

Cited by 72 publications

References 20 publications

8-Hydroxyquinolines Are Boosting Agents of Copper-Related Toxicity in Mycobacterium tuberculosis

8-Hydroxyquinolines Are Boosting Agents of Copper-Related Toxicity in Mycobacterium tuberculosis

Membrane compartments and purinergic signalling: P2X receptors in neurodegenerative and neuroinflammatory events

Clioquinol promotes the degradation of metal-dependent amyloid-β (Aβ) oligomers to restore endocytosis and ameliorate Aβ toxicity

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