Zinc Ionophore Research Articles

Supramolecular Self-Assembled Hydrogel for Antiviral Therapy through Glycyrrhizic Acid-Enhanced Zinc Absorption and Intracellular Accumulation.

Respiratory syncytial virus (RSV) is a common pathogen that causes respiratory infections in infants and children worldwide, significantly impacting hospitalization rates in this age group. Zinc ions are considered to have broad-spectrum antiviral potential against RNA viruses, including RSV. However, poor organism absorption and low intracellular accumulation of zinc require repeated high-dose supplementation, which may lead to unnecessary toxic side effects. In this research, a Zn2+-mediated glycyrrhizinic acid (GA)-based hydrogel (ZnGA Gel) was introduced and potentially developed to be a clinically available drug candidate for RSV therapy. ZnGA Gel was fabricated based on the cooperation of two potential RSV inhibiting molecules (Zn2+ and GA), where Zn2+ promoted self-assembly of GA and reduced its gel concentration and GA promoted zinc absorption and distribution in lung tissue in vivo. The facile construction of supramolecular hydrogel by the self-assembled coordination complex made it an injectable, temperature-sensitive, and pH-responsive controlled-release drug delivery for Zn2+. Most importantly, GA was observed to enhance organism absorption and intracellular accumulation of Zn2+ and was identified as a zinc ionophore for the first time. GA can colonize on the cell membrane and disturb cell membrane potential, resulting in an enhanced cell membrane permeability. In the presence of GA, more than 4.7-fold increasing Zn2+ concentrations materialized in the intracellular cytoplasm, compared to Zn2+ alone administration. This intracellular Zn2+ accumulation directly boosted the antiviral activities through improved inhibition of RSV replication-associated proteins and significantly inhibited RSV replication. Oral administration of ZnGA Gel on the RSV-infected mice model achieved an ideal therapeutic effect by effectively lowering viral load in the lungs, alleviating lung injury symptoms, and reducing inflammatory cell infiltration at pathological sites. The mechanism involved the inhibition of RSV replication-related proteins, aligning with our in vitro results. Additionally, ZnGA Gel had demonstrated biocompatibility, and reasonable supplementation of zinc was acceptable and effective for infants and children in clinical practice. Hence, the ZnGA Gel developed by us holds promise as an effective anti-RSV medicine in the future.

Protective effect of zinc against A2E-induced toxicity in ARPE-19 cells: Possible involvement of lysosomal acidification

A key pathogenic mechanism of dry age-related macular degeneration (AMD) is lysosomal dysfunction in retinal pigment epithelium (RPE) cells, which results in the accumulation of lipofuscins such as A2E (N-retinylidene-N-retinylethanolamine) that further compromises lysosomal function. This vicious cycle leads to cell death and poor visual acuity. Here, we established an in vitro model of AMD by treating a human RPE cell line (ARPE-19) with A2E and examined whether raising zinc levels confers protective effects against lysosomal dysfunction and cytotoxicity. MTT assay showed that A2E induced apoptosis in ARPE-19 cells. pHrodo™ Red fluorescence staining showed that lysosomal pH increased in A2E-treated ARPE-19 cells. Treatment with a zinc ionophore (clioquinol) reduced A2E accumulation, restored lysosomal pH to the acidic range, and reduced A2E-induced cell death, all of which were reversed by the addition of a zinc chelator (TPEN). Consistent with the in vitro results, subretinal injections of A2E in mouse eyes resulted in the death of RPE cells as well as lysosomal dysfunction, all of which were reversed by co-treatment with clioquinol. Our results suggest that restoring the levels of intracellular zinc, especially in lysosomes, would be helpful in mitigating A2E-induced cytotoxic changes including lysosomal dysfunction in RPE cells in the pathogenesis of AMD.

The zinc ion concentration dynamically regulated by an ionophore in the outer Helmholtz layer for stable Zn anode

The Zn dendrite limits the practical application of aqueous zinc-ion batteries in the large-scale energy storage systems. To suppress the growth of Zn dendrites, a zinc ionophore of hydroxychloroquine (defined as HCQ) applied in vivo treatment is investigated as the electrolyte additive. HCQ dynamically regulates zinc ion concentration in the outer Helmholtz layer, promoting even Zn plating at the anode/electrolyte interface. This is evidenced by the scanning electron microscopy, which delivers planar Zn plating after cycling. It is further supported by the X-ray diffraction spectroscopy, which reveals the growth of Zn (002) plane. Additionally, the reduced production of H2 during Zn plating/stripping is detected by the in-situ differential electrochemical mass spectrometry (DEMS), which shows the resistance of Zn (002) to hydrogen evolution reaction. The mechanism of dynamic regulation for zinc ion concentration is demonstrated by the in-situ optical microscopy. The hydrated zinc ion can be further plated more rapidly to the uneven location than the case in other regions, which is resulted from the dynamic regulation for zinc ion concentration. Therefore, the uniform Zn plating is formed. A cycling life of 1100 h is exhibited in the Zn||Zn symmetric cell at 1.6 mA cm−2 with the capacity of 1.6 mAh cm−2. The Zn||Cu battery exhibits a cycling life of 200 cycles at 4 mA cm−2 with a capacity of 4 mAh cm−2 and the average Coulombic efficiency is larger than 99 %. The Zn||VO2 battery with HCQ modified electrolyte can operate for 1500 cycles at 4 A g−1 with a capacity retention of 90 %. This strategy in the present work is wished to advance the development of zinc-ion batteries for practical application.

Zinc Ionophore Pyrithione Mimics CD28 Costimulatory Signal in CD3 Activated T Cells.

Zinc is an essential trace element that plays a crucial role in T cell immunity. During T cell activation, zinc is not only structurally important, but zinc signals can also act as a second messenger. This research investigates zinc signals in T cell activation and their function in T helper cell 1 differentiation. For this purpose, peripheral blood mononuclear cells were activated via the T cell receptor-CD3 complex, and via CD28 as a costimulatory signal. Fast and long-term changes in intracellular zinc and calcium were monitored by flow cytometry. Further, interferon (IFN)-γ was analyzed to investigate the differentiation into T helper 1 cells. We show that fast zinc fluxes are induced via CD3. Also, the intracellular zinc concentration dramatically increases 72 h after anti-CD3 and anti-CD28 stimulation, which goes along with the high release of IFN-γ. Interestingly, we found that zinc signals can function as a costimulatory signal for T helper cell 1 differentiation when T cells are activated only via CD3. These results demonstrate the importance of zinc signaling alongside calcium signaling in T cell differentiation.

Antiviral and Cytoprotective Effect of Zinc (Yasad Bhasma) Based Nanoformulations Against Bovine Coronavirus.

Ayurvedic medicine utilizes metal-based preparations, known as bhasmas, to treat various health conditions. Yasad bhasma (YB), a zinc-based ayurvedic preparation, shows promise as a potential candidate for developing zinc-based nanomedicines with anti-inflammatory and antioxidant properties. In this study, we synthesized a formulation combining YB and hydroxychloroquine (HC) as a zinc ionophore (YBHC) and investigated its biocompatibility and antiviral effects against buffalo calf coronavirus (BCoV) in Vero cells. Our results demonstrated that the formulation exhibited good conformity and enhanced cell proliferation compared to untreated cells. Additionally, no cytopathic effects were observed in BCoV-infected Vero cells treated with YBHC and YB, while infected control cells exhibited cytopathic effects. YB showed cytoprotection by promoting epithelial tissue turnover. We further explored whether YB/YBHC exerted a lysosomotropic effect to produce antiviral effects on coronavirus-adapted Vero cells, but no cell internalization was observed. In addition to the synergistic antiviral effect of YB and HC, YB may play a vital role in rejuvenating affected tissues.

The 8-hydroxyquinoline derivative, clioquinol, is an alpha-1 adrenoceptor antagonist

Clioquinol (5-chloro-7-iodo-8-hydroxyquinoline) is an antimicrobial agent whose actions as a zinc or copper ionophore and an iron chelator revived the interest in similar compounds for the treatment of fungal and bacterial infections, neurodegeneration and cancer. Recently, we reported zinc ionophores, including clioquinol, cause vasorelaxation in isolated arteries through mechanisms that involve sensory nerves, endothelium and vascular smooth muscle. Here, we report that clioquinol also uniquely acts as a competitive alpha-1 (α1) adrenoceptor antagonist. We employed ex vivo functional vascular contraction and pharmacological techniques in rat isolated mesenteric arteries, receptor binding assays using stabilized solubilized α1 receptor variants, or wild-type human α1-adrenoceptors transfected in COS-7 cells (African green monkey kidney fibroblast-like cells), and molecular dynamics homology modelling based on the recently published α1A adrenoceptor cryo-EM and α1B crystal structures. At higher concentrations, all ionophores including clioquinol cause a non-competitive antagonism of agonist-mediated contraction due to intracellular zinc delivery, as reported previously. However, at lower concentration ranges, clioquinol has an additional mechanism of competitively inhibiting α1-adrenoceptors that contributes to decreasing vascular contractility. Molecular dynamic simulation showed that clioquinol binds stably to the orthosteric binding site (Asp106) of the receptor, confirming the structural basis for competitive α1-adrenoceptor antagonism by clioquinol.

Supramolecular Membrane Chemistry in the Langton Group

AbstractThis invited Team Profile was created by the Langton group in the Department of Chemistry, University of Oxford (UK). They recently published an article on a synthetic supramolecular signaling system, in which light is used to initiate the release of diffusible chemical signals from one population of vesicles to another. This triggers transmembrane cation transport in the receiver vesicles and amplifies the signal, in a manner reminiscent of signaling mechanisms in biology. “Inter‐Vesicle Signal Transduction Using a Photo‐responsive Zinc Ionophore”, S. A. Gartland, T. G. Johnson, E. Walkley, M. J. Langton Angew. Chem. Int. Ed. 2023, 62, e202309080.

Supramolecular Membrane Chemistry in the Langton Group.

This invited Team Profile was created by the Langton group in the Department of Chemistry, University of Oxford (UK). They recently published an article on a synthetic supramolecular signaling system, in which light is used to initiate the release of diffusible chemical signals from one population of vesicles to another. This triggers transmembrane cation transport in the receiver vesicles and amplifies the signal, in a manner reminiscent of signaling mechanisms in biology. "Inter-Vesicle Signal Transduction Using a Photo-responsive Zinc Ionophore", S. A. Gartland, T. G. Johnson, E. Walkley, M. J. Langton Angew. Chem. Int. Ed. 2023, 62, e202309080.

SAT019 Ligand-independent Signaling And Migration Of Breast Cancer Cells Overexpressing Membrane Androgen Receptor, ZIP9

Abstract Disclosure: P. Thomas: None. The zinc transporter ZIP9 also functions as a membrane androgen receptor (mAR) that mediates androgen-dependent rapid signaling and pro- or anti-apoptotic, proliferative, and migratory responses in fish, rodent, and human cells. Testosterone activation of ZIP9 in two triple-negative breast cancer cell lines, MDA-MB-468 cells and MDA-MB-231 cells transfected with ZIP9 (231-ZIP9), induces G-protein-dependent second messenger signaling and increases in intracellular free zinc. However, the relative importance of these two signaling pathways in the regulation of pro- and anti-tumorigenic responses in these cell lines is unclear because both androgen signaling and zinc status influence tumorigenesis in breast tissues. The effects of overexpression of ZIP9 on free zinc status, G protein- and zinc-dependent regulation of migration, and migration marker expression in 231-ZIP9 cells in the absence of testosterone were compared to those observed in MDA-MB-231 cells transfected with vector alone (231-vect). Migration and invasion of 231-ZIP9 cells were significantly increased after 24-48 hr culture in serum-free media compared to 231-vect cells which was accompanied by a significant increase in free zinc levels. Treatment of 231-vect cells with a zinc ionophore also increased migration, whereas migration of 231-ZIP9 cells was attenuated by treatment with an intracellular zinc chelator, TPEN. Expression of the migration markers, MYL9 and CYR61, was increased in 231-ZIP9 after 24-48 hr culture, whereas expression of apoptotic markers was decreased compared to 231-vect controls. Proximity Ligation Analysis revealed that ZIP9 is closely associated with a stimulatory G protein (Gs) in 231-ZIP9 cells which is consistent with the finding that treatment with the adenylyl cyclase (AC) stimulator forskolin, further increased migration marker expression and migration compared to vehicle controls, whereas the PKA inhibitor, H-89, attenuated these responses as well as the increase in free zinc concentrations. Knockdown of ZIP9 expression in MDA-MB-468 cells which express relatively high levels of ZIP9 with siRNA decreased cell migration and invasion as well as free zinc levels, confirming a role of unliganded ZIP9 in migration in another breast cancer cell line. Treatment of 231-ZIP9 cells with 100 nM testosterone further stimulated CYR61 and MYL9 expression and cell migration which were blocked by co-treatment with a Gs inhibitor and TPEN. The results indicate that high ZIP9 expression in breast cancer cells causes androgen-independent increased cell migration and invasion which in 231-ZIP9 cells is through Gs/mAC/PKA-mediated increases in intracellular zinc concentrations and upregulation of MYL9 and CYR-61 expression. Furthermore, the results suggest that testosterone-dependent signaling through ZIP9 acts through the same pathways to further enhance signaling and migration. Presentation: Saturday, June 17, 2023

Ligand-independent signaling and migration of breast cancer cells expressing membrane androgen receptor, ZIP9 (SLC39A9)

Zinc transporter ZIP9 is also a membrane androgen receptor that mediates androgen-dependent zinc and G-protein signaling to modulate tumorigenic responses in cancer cells. It is unclear whether unliganded ZIP9 causes similar responses. ZIP9 overexpression in MDA-MB-231 breast cancer cells (ZIP9 cells) increased zinc levels and cell migration/invasion which was mimicked with a zinc ionophore and attenuated with a zinc chelator, suggesting these tumorigenic responses are zinc-dependent. Expression of migration markers MYL9 and CYR61 was elevated in ZIP9 cells and further increased together with cell migration by forskolin treatment and blocked with H-89, indicating they are mediated through an AC/PKA pathway. Knockdown of ZIP9 expression in MDA-MB-468 cells decreased cell migration/invasion, migration markers and zinc levels, confirming similar roles of unliganded ZIP9 in another breast cancer cell line. Testosterone treatment further increased migration, biomarker expression and zinc in ZIP9 cells, suggesting it may act through similar pathways to induce tumorigenic responses.

Inter‐Vesicle Signal Transduction Using a Photo‐Responsive Zinc Ionophore

AbstractTransmission of chemical information between cells and across lipid bilayer membranes is of profound significance in many biological processes. The design of synthetic signalling systems is a critical step towards preparing artificial cells with collective behaviour. Here, we report the first example of a synthetic inter‐vesicle signalling system, in which diffusible chemical signals trigger transmembrane ion transport in a manner reminiscent of signalling pathways in biology. The system is derived from novel ortho‐nitrobenzyl and BODIPY photo‐caged ZnII transporters, in which cation transport is triggered by photo‐decaging with UV or red light, respectively. This decaging reaction can be used to trigger the release of the cationophores from a small population of sender vesicles. This in turn triggers the transport of ions across the membrane of a larger population of receiver vesicles, but not across the sender vesicle membrane, leading to overall inter‐vesicle signal transduction and amplification.

Inter-Vesicle Signal Transduction Using a Photo-Responsive Zinc Ionophore.

Transmission of chemical information between cells and across lipid bilayer membranes is of profound significance in many biological processes. The design of synthetic signalling systems is a critical step towards preparing artificial cells with collective behaviour. Here, we report the first example of a synthetic inter-vesicle signalling system, in which diffusible chemical signals trigger transmembrane ion transport in a manner reminiscent of signalling pathways in biology. The system is derived from novel ortho-nitrobenzyl and BODIPY photo-caged ZnII transporters, in which cation transport is triggered by photo-decaging with UV or red light, respectively. This decaging reaction can be used to trigger the release of the cationophores from a small population of sender vesicles. This in turn triggers the transport of ions across the membrane of a larger population of receiver vesicles, but not across the sender vesicle membrane, leading to overall inter-vesicle signal transduction and amplification.

Quinoline Thiourea-Based Zinc Ionophores with Antibacterial Activity.

The increasing resistance of bacteria to commercially available antibiotics threatens patient safety in healthcare settings. Perturbation of ion homeostasis has emerged as a potential therapeutic strategy to fight against antibacterial resistance and other channelopathies. This study reports the development of 8-aminoquinoline (QN) derivatives and their transmembrane Zn2+ transport activities. Our findings showed that a potent QN-based Zn2+ transporter exhibits promising antibacterial properties against Gram-positive bacteria with reduced hemolytic activity and cytotoxicity to mammalian cells. Furthermore, this combination showed excellent in vivo efficacy against Staphylococcus aureus. Interestingly, this combination prevented bacterial resistance and restored susceptibility of gentamicin and methicillin-resistant S. aureus to commercially available β-lactam and other antibiotics that had lost their activity against the drug-resistant bacterial strain. Our findings suggest that the transmembrane transport of Zn2+ by QN derivatives could be a promising strategy to combat bacterial infections and restore the activity of other antibiotics.

Synergistic Effect of Zinc-Chitosan Nanoparticles and Hydroxychloroquine to Inhibit Buffalo Coronavirus

Zinc ions can hinder the synthesis of proteins required for accomplishing several stages of the viral life cycle. The intracellular zinc concentration can be increased by using zinc ionophores which transport zinc ions into the cells and hinder viral replication. (Hydroxy)chloroquine is an example of a zinc ionophore, but both zinc and (hydroxy)chloroquine can be toxic to the host organism. The nanocarriers may serve as camouflage to evade the adverse effects of drugs, chemicals, and nanoparticles on the host. We formulated ZnO nanoparticles with flower-like morphology (ZnONFs). It was further decorated with chitosan along with hydroxychloroquine (as a zinc ionophore) (CHCZnO NPs). We have chosen the cationic polymer chitosan since it is biocompatible, biodegradable and binds easily with the cells, and enhances the transport of drugs across cell membranes. The formulation was investigated for size, shape, surface charge, and interaction of chemicals used. We evaluated the formulations for cytotoxicity, and biocompatibility in embryonated chicks and their efficacy against bovine coronavirus (BCoV) isolated from a buffalo calf, and pneumo-enteric coronaviruses isolated from a buffalo calf with promising results in comparison to ZnONFs/hydroxychloroquine alone. Furthermore, we elucidate the mechanism underlying the lysosomotropic effect of various formulations on Vero cells infected with the buffalo coronavirus.

Chloroquine disrupts zinc storage granules in primary Malpighian tubule cells of Drosophila melanogaster.

Contrasting reports exist in the literature regarding the effect of chloroquine treatment on cellular zinc uptake or secretion. Here, we tested the effect of chloroquine administration in the Drosophila model organism. We show that larvae grown on a diet supplemented with 2.5mg/ml chloroquine lose up to 50% of their stored zinc and around 10% of their total potassium content. This defect in chloroquine-treated animals correlates with the appearance of abnormal autophagolysosomes in the principal cells of the Malpighian tubules, where zinc storage granules reside. We further show that the reported increase of Fluozin-3 fluorescence following treatment of cells with 300 μM chloroquine for 1 h may not reflect increased zinc accumulation, since a similar treatment in Madin-Darby canine kidney cells results in a 36% decrease in their total zinc content. Thus, chloroquine should not be considered a zinc ionophore. Zinc supplementation plus chloroquine treatment restored zinc content both in vivo and in vitro, without correcting autophagic or other ionic alterations, notably in potassium, associated with the chloroquine treatment. We suggest that chloroquine or hydroxychloroquine administration to patients could reduce intracellular zinc storage pools and be part of the drug's mechanism of action.

Hydroxychloroquine Does Not Function as a Direct Zinc Ionophore

Drug-mediated correction of abnormal biological zinc homeostasis could provide new routes to treating neurodegeneration, cancer, and viral infections. Designing therapeutics to facilitate zinc transport intracellularly is hampered by inadequate concentrations of endogenous zinc, which is often protein-bound in vivo. We found strong evidence that hydroxychloroquine, a drug used to treat malaria and employed as a potential treatment for COVID-19, does not bind and transport zinc across biological membranes through ionophoric mechanisms, contrary to recent claims. In vitro complexation studies and liposomal transport assays are correlated with cellular zinc assays in A549 lung epithelial cells to confirm the indirect mechanism of hydroxychloroquine-mediated elevation in intracellular zinc without ionophorism. Molecular simulations show hydroxychloroquine-triggered helix perturbation in zinc-finger protein without zinc chelation, a potential alternative non-ionophoric mechanism.

Rational Design of Silicon‐Based Zinc Ionophores

AbstractIonophores transport ions across biological membranes and have wide‐ranging applications, but a platform for their rapid development does not exist. We report a platform for developing ionophores from metal‐ion chelators, which are readily available with wide‐ranging affinities and specificities, and structural data that can aid rational design. Specifically, we fine‐tuned the binding affinity and lipophilicity of a ZnII‐chelating ligand by introducing silyl groups proximal to the ZnII‐binding pocket, which generated ionophores that performed better than most of the currently known ZnII ionophores. Furthermore, these silicon‐based ionophores were specific for ZnII over other metals and exhibited better antibacterial activity and less toxicity to mammalian cells than several known ZnII ionophores, including pyrithione. These studies establish rational design principles for the rapid development of potent and specific ionophores and a new class of antibacterial agents.

Rational Design of Silicon-Based Zinc Ionophores.

Ionophores transport ions across biological membranes and have wide-ranging applications, but a platform for their rapid development does not exist. We report a platform for developing ionophores from metal-ion chelators, which are readily available with wide-ranging affinities and specificities, and structural data that can aid rational design. Specifically, we fine-tuned the binding affinity and lipophilicity of a ZnII -chelating ligand by introducing silyl groups proximal to the ZnII -binding pocket, which generated ionophores that performed better than most of the currently known ZnII ionophores. Furthermore, these silicon-based ionophores were specific for ZnII over other metals and exhibited better antibacterial activity and less toxicity to mammalian cells than several known ZnII ionophores, including pyrithione. These studies establish rational design principles for the rapid development of potent and specific ionophores and a new class of antibacterial agents.

Inhibition of Respiratory RNA Viruses by a Composition of Ionophoric Polyphenols with Metal Ions

Controlling the infectivity of respiratory RNA viruses is critical, especially during the current SARS-CoV-2 pandemic. There is an unmet need for therapeutic agents that can reduce viral replication, preferably independent of the accumulation of viral mutations. Zinc ions have an apparent activity as modulators of intracellular viral RNA replication and thus, appear attractive in reducing viral RNA load and infectivity. However, the intracellular concentration of zinc is usually too low for achieving an optimal inhibitory effect. Various herbal polyphenols serve as excellent zinc ionophores with known antiviral properties. Here, we combined zinc picolinate with a collection of flavonoids, representing commonly used polyphenols. Copper was added to avoid ionic imbalance during treatment and to improve efficacy. Each component separately, as well as their combinations, did not interfere with the viability of cultured A549, H1299, or Vero cells in vitro as determined by MTT assay. The safe combinations were further evaluated to determine antiviral activity. Fluorescence-activated cell sorting and quantitative polymerase chain reaction were used to evaluate antiviral activity of the combinations. They revealed a remarkable (50–95%) decrease, in genome replication levels of a diverse group of respiratory RNA viruses, including the human coronavirus OC43 (HCoV-OC43; a betacoronavirus that causes the common cold), influenza A virus (IAV, strain A/Puerto Rico/8/34 H1N1), and human metapneumovirus (hMPV). Collectively, our results offer an orally bioavailable therapeutic approach that is non-toxic, naturally sourced, applicable to numerous RNA viruses, and potentially insensitive to new mutations and variants.

Development of Therapeutic and Prophylactic Zinc Compositions for Use against COVID-19: A Glimpse of the Trends, Inventions, and Patents.

Zinc is an essential nutrient for human health; it is involved in the catalytic, structural, and regulatory functions of the human cellular system. Different compositions of zinc, as well as its pharmaceutically acceptable salts, are available on the market. Recent studies have demonstrated the role of zinc in combating COVID-19. It has been determined that zinc prevents the entry of SARS-CoV-2 into cells by lowering the expression of ACE-2 receptors and inhibiting the RNA-dependent RNA polymerase of SARS-CoV-2. Zinc also prevents the cytokine storm that takes place after the entry of SARS-CoV-2 into the cell, via its anti-inflammatory activity. The authors believe that no study has yet been published that has reviewed the trends, inventions, and patent literature of zinc compositions to treat/prevent COVID-19. Accordingly, this review has been written in order to fill this gap in the literature. The information about the clinical studies and the published patents/patent applications was retrieved from different databases. This review covers patent literature on zinc compositions up to 31 January 2022. Many important patents/patent applications for zinc-based compositions filed by innovative universities and industries were identified. The patent literature revealed zinc compositions in combination with zinc ionophores, antioxidants, antivirals, antibiotics, hydroxychloroquine, heparin, ivermectin, and copper. Most of these studies were supported by clinical trials. The patent literature supports the potential of zinc and its pharmaceutical compositions as possible treatments for COVID-19. The authors believe that countless zinc-based compositions are still unexplored, and there is an immense opportunity to evaluate a considerable number of the zinc-based compositions for use against COVID-19.