Abstract
The importance of zinc in biology has gained greater recognition in recent years due to its essential contributions to the function of many endogenous enzymes. Disruption of zinc homeostasis may be useful in treating pathological conditions, such as Alzheimer’s, and for antiviral purposes. Despite the growth of knowledge and increased interest in zinc, little is known about the structure and function of zinc ionophores. In this study we analyse the Cambridge Structural Database and solution complexation studies found in the literature to identify key functional groups which may confer zinc ionophorism. Pharmaceuticals, nutraceuticals and amino acids with these functionalities were selected to enable us to explore the translatability of ionophoric activity from in vitro assays to cellular systems. We find that although certain species may complex to zinc in the solid and solution states, and may carry ions across simple membrane systems, this does not necessarily translate into ionophoric activity. We propose that the CSD can help refine key functionalities but that ionophoric activity must be confirmed in cellular systems.
Highlights
IntroductionPublisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations
Hydroxyl groups account for the majority of zinc binding to oxygen (n = 6247/10,283; 61%), and phenol functionalities make up a significant fraction of this group (n = 1548)
Liposomal assays are important as a screening tool, they have limitations, e.g., they may underestimate ionophorism where another counter-ion is important to the ionophoric mechanism or overestimate ionophorism where efflux pumps and other biological species can neutralize the accumulation of ions intracellularly
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. The complexation of pharmaceuticals with metals is one strategy to improve the therapeutic and physicochemical properties of selected pharmaceuticals. Many products available on the market are produced using this method: Pepto-bismol® (salicylic acid and bismuth), Polaprezinc® (carnosine and zinc) and Zyneryt® (erythromycin and zinc acetate). It is unclear whether the metals involved in complexation have favorable properties in their own right or the therapeutic activity is conferred through synergy. Reformulation of drugs as metal ion complexes could lead to new, cost-effective therapeutic opportunities (as the safety characteristics for repurposed pharmaceuticals are well established relative to novel compounds)—a consideration that is gaining increased importance as the cost of drug development is expected to exceed $3 bn if it continues to follow recent trends [1]
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