Coordination chemistry suggests that independently observed benefits of metformin and Zn against COVID-19 are not independent.

Independent trials indicate that either oral Zn or metformin can separately improve COVID-19 outcomes by approximately 40%. Coordination chemistry predicts a mechanistic relationship and therapeutic synergy. Zn deficit is a known risk factor for both COVID-19 and non-infectious inflammation.

Biguanide is a modifiable pharmacophore for recruitment of endogenous Zn to inhibit cysteinyl cathepsins: review and implications.

Excessive activities of cysteinyl cathepsins (CysCts) contribute to the progress of many diseases; however, therapeutic inhibition has been problematic. Zn is a natural inhibitor of proteases with CysHis dyads or CysHis(Xaa) triads. Biguanide forms bidentate metal complexes through the two imino nitrogens.

Lysosomal metal, redox and proton cycles influencing the CysHis cathepsin reaction.

In the 1930's pioneers discovered that maximal autolysis in tissue homogenates requires metal chelator, sulfhydryl reducing agent and acid pH. However, metals, reducing equivalents and protons (MR&P) have been overlooked as combined catalytic controls. Three categories of lysosomal machinery drive three distinguishable cycles importing and exporting MR&P.

The lysosome among targets of metformin: new anti-inflammatory uses for an old drug?

Background: Rheumatoid arthritis and type-2 diabetes exhibit progressive co-morbidity. Chloroquine (CQ) reportedly improves both. CQ inhibits lysosomal function in cultured cells at supra-therapeutic concentration; however, this is doubted as target mechanism.

Is dihydrolipoic acid among the reductive activators of parasite CysHis proteases?

Activities of mature CysHis proteases depend upon relative rates of oxidations vs. reductions of catalytic sulfur by multiple enzymatic and non-enzymatic reactions. CysHis peptidolysis is inhibited by Fe3+ but not Fe2+.

Responsiveness of parasite Cys His proteases to iron redox.

Plasmodium falciparum growth can be opposed in erythrocyte culture or in vivo by nonselective inhibitors of CysHis proteases or pro-oxidative drugs, which elevate erythrocyte Fe(3+). However, no relationship between Fe redox and CysHis protease inhibition has been suggested. Here, mature falcipain-2 was found to be inhibited by relevant concentrations of Fe(3+) but not Fe(2+) in the presence of excess GSH or DTT.

The transfer of reductive energy and pace of proteome turnover: a theory of integrated catabolic control.

Hundreds of cell proteins undergo reversible transitions among redox states. Coordinate control and common functions served by redox-modified proteins are unknown. The suspect "redox code" integrating metabolome, proteome, and genome remains undefined.

Cys-His proteases are among the wired proteins of the cell.

Integrated cell protein degradation can be paced by the transfer of reductive energy, as revealed by experimental agents of informative actions. The peptidolytic pair of Cys-His proteases can undergo oxidative reactions to inactive derivatives and inhibitory metal binding. Proton-dependent ionizations can modify ongoing activity.

Redox pacing of proteome turnover: influences of glutathione and ketonemia.

In early starvation tissue protein degradation increases, however in later starvation proteolysis declines so as to pace gradual atrophy during synthetic failure. Secondary decline of proteolytic pathways under progressive nutritional desperation is unexplained. After several days of starvation tissue GSH is partly depleted and GSSG/GSH is increased, followed by onset of ketonemia from fat breakdown.

Antidiabetic and antimalarial biguanide drugs are metal-interactive antiproteolytic agents.

Various biguanide derivatives are used as antihyperglycemic and antimalarial drugs (e.g., 1,1-dimethyl biguanide (metformin), phenylethyl biguanide (phenformin), N-(4-chlorophenyl)-N'-(isopropyl)-imidodicarbonimidic diamide (proguanil)); however, no common mechanism has been suggested in these controversial therapeutic actions.

Cathepsin B responsiveness to glutathione and lipoic acid redox.

Some subcomponents of cell protein degradation exhibit an unexplained reductive energy requirement; and diverse cysteine proteases are among multiple effector mechanisms requiring reduction. Present studies investigated whether cathepsin B activity is graded in response to (a) reduced glutathione (GSH) and dihydrolipoic acid (DHLA) concentrations, (b) their redox ratios, and (c) their differential potencies and efficacies. Purified bovine cathepsin B activity was assayed with carbobenzyloxy-Arg-Arg-aminomethylcoumarin by standard methods following inactivation by spontaneous air oxidation.