ZIP14 Inhibitors

Chemical inhibitors of ZIP14 include a variety of chelating agents that sequester metal ions, which are essential substrates for the function of ZIP14. TPEN, DTPA, EDTA, and EGTA are all potent chelators with high affinity for metal ions, such as zinc and iron, which ZIP14 transports. By binding these metal ions, these chelating agents reduce the availability of the protein's substrates, thus inhibiting the metal ion transport activity of ZIP14. Specifically, TPEN is a particularly strong chelator of zinc, which is a crucial substrate for ZIP14, and its sequestration of zinc can inhibit the protein's ability to transport this metal across cellular membranes. Similarly, DTPA and EDTA have broad metal-binding capabilities, which include the chelation of zinc and iron, again leading to inhibition of ZIP14 by limiting the protein's access to these essential ions.

Further extending the list of chemical inhibitors, Phenanthroline and Clioquinol also engage in metal chelation. Phenanthroline has a strong affinity for iron and can also bind zinc, which can interfere with the metal transport function of ZIP14. Clioquinol chelates both zinc and copper, and this action is likely to inhibit ZIP14 by reducing the concentration of these ions available for transport. Additionally, the alteration of intracellular ion dynamics via calcium channel modulators such as Bay K8644, Verapamil, and Nicardipine can indirectly inhibit ZIP14. These agents perturb the balance of metal ions by affecting calcium channels, which, in turn, could inhibit ZIP14 by disrupting the cellular ion homeostasis that is partly regulated by the protein. Lastly, Amiloride, a sodium channel inhibitor, indirectly affects ZIP14 function by altering cellular ion gradients and transportation mechanisms upon which ZIP14's activity can depend.