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Hydroxychloroquine Does Not Function as a Direct Zinc Ionophore.

Oisín N Kavanagh1,2,3,4,5, Shayon Bhattacharya1,6, Luke Marchetti1,4

  • 1SSPC, The Science Foundation Ireland Research Centre for Pharmaceuticals, V94 T9PX Limerick, Ireland.

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Summary
This summary is machine-generated.

Hydroxychloroquine does not transport zinc via ionophores, contrary to claims. This study reveals an indirect mechanism for hydroxychloroquine increasing intracellular zinc, important for neurodegeneration and cancer research.

Keywords:
COVID-19clioquinolhydroxychloroquineionophorezinc

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Area of Science:

  • Biochemistry
  • Molecular Biology
  • Pharmacology

Background:

  • Abnormal zinc homeostasis is implicated in neurodegeneration, cancer, and viral infections.
  • Intracellular zinc delivery is challenging due to low endogenous zinc levels, often protein-bound.
  • Hydroxychloroquine has been proposed to transport zinc intracellularly.

Purpose of the Study:

  • To investigate the mechanism by which hydroxychloroquine affects intracellular zinc levels.
  • To determine if hydroxychloroquine acts as a zinc ionophore.
  • To explore alternative non-ionophoric mechanisms for hydroxychloroquine's effect on zinc.

Main Methods:

  • In vitro complexation studies.
  • Liposomal transport assays.
  • Cellular zinc assays in A549 lung epithelial cells.
  • Molecular simulations of hydroxychloroquine interaction with zinc-finger proteins.

Main Results:

  • Hydroxychloroquine does not bind and transport zinc across biological membranes via ionophoric mechanisms.
  • Evidence supports an indirect mechanism for hydroxychloroquine-mediated elevation of intracellular zinc.
  • Molecular simulations indicate hydroxychloroquine perturbs zinc-finger protein structure without direct zinc chelation.

Conclusions:

  • The proposed ionophoric mechanism of hydroxychloroquine for zinc transport is not supported.
  • Hydroxychloroquine influences intracellular zinc through a non-ionophoric pathway.
  • Understanding this indirect mechanism is crucial for developing zinc-based therapeutics for various diseases.