Zinc ionophores: chemistry and biological applications

Zinc pyrithione is a potent inhibitor of PLPro and cathepsin L enzymes with ex vivo inhibition of SARS-CoV-2 entry and replication

“…In addition, zinc pyrithione 1a also inhibited SARS-CoV-2 M Pro with IC 50 values in the submicromolar range (IC 50 =0.9687 µM 29 and 0.1 µM 30 ). The promising inhibition of cathepsin L and PL Pro 69 by zinc complexes, but not by ligands alone, could be attributed to the thiophilic character of zinc 59 and its binding to cysteine residues in the active sites of the aforementioned proteases. An interesting study discussing the influence of zinc coordination sphere on the reactivity of the metal centre showed, that certain type of a ligand affects Lewis acidity as well as hard/soft character of the zinc.…”

Zinc pyrithione is a potent inhibitor of PLPro and cathepsin L enzymes with ex vivo inhibition of SARS-CoV-2 entry and replication

“…Ionophores, molecules that enable the transport of metal ions across a lipid cell membrane, increase zinc uptake and facilitate zinc absorption, thus combating COVID-19. 13,[52][53][54] In a multi-center study testing zinc sulphate and hydroxychloroquine as potential treatments, increased hospital discharge and decreased in-hospital mortality were observed. 55 However, hydroxychloroquine as a therapeutic against COVID-19 should be considered with great caution as it may significantly increase the risk of cardiac arrhythmias.…”

“…25,26 In addition, zinc pyrithione 1a also inhibited SARS-CoV-2 M Pro with IC50 values in the submicromolar range (IC50 = 0.9687 µM 28 and 0.1 µM 29 ). The promising inhibition of cathepsin L and PL Pro by zinc complexes, but not by ligands alone, could be attributed to the thiophilic character of zinc 54 and its binding to cysteine residues in the active sites of the aforementioned proteases. It is worth noting that Wang et al recently reported that a mixture containing colloidal bismuth subcitrate can significantly inactivate viral cysteine proteases by binding the key cysteine residue in the active sites of PL Pro and M Pro , thus providing a potential treatment to combat SARS-CoV-2.…”

“…25,26 In addition, zinc pyrithione 1a also inhibited SARS-CoV-2 M Pro with IC 50 values in the submicromolar range (IC 50 = 0.9687 μM 28 and 0.1 μM 29 ). The promising inhibition of cathepsin L and PL Pro by zinc complexes, but not by ligands alone, could be attributed to the thiophilic character of zinc 54 and its binding to cysteine residues in the active sites of the aforementioned proteases. It is worth noting that Wang et al .…”

The Molecular Basis for Zinc Bioavailability

“…The amount of oral zinc needed for the treatment of a mouse model of AE is also reduced when zinc is provided with the dihalo-hydroxyquinoline drug clioquinol [ 98 ]. Several hydrophobic zinc ionophores are capable of delivering zinc across the cell membrane without a transporter, a property that has attracted attention to their potential therapeutic use in the treatment of infections, cancer, and neurological diseases [ 99 , 100 , 101 , 102 ]. Similarly, zinc complexes with EDTA cross the apical membrane of luminal enterocytes intact.…”