Hydroxychloroquine Does Not Function as a Direct Zinc Ionophore.

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.