Construction of a water-soluble, oxygen-tolerant, and acid-stable synthetic H2 production catalyst is vital for the development of an economic and user-friendly H2-based renewable energy infrastructure. Natural enzyme hydrogenases exhibit excellent energy-efficient H2 production activity. However, fragility of the overall protein structure has restricted their sustainable and practical application. Among the synthetic functional models of hydrogenase, cobaloxime-based complexes offer O2-insensitivity. However, they are only active near neutral conditions with moderate rates and poor aqueous solubility properties. Here, in this work, we have specifically stationed a series of enzyme-inspired, multicomponent outer coordination sphere components around the cobaloxime core to simultaneously improve its catalytic rate, aqueous solubility, and activity even under acidic conditions. We have also established that cobaloximes display catalytic H2 production via two independent mechanisms: (i) Co­(II)-centric and (ii) Co­(I)-centric. Initial Co­(II)-centric H2 evolution occurred at a relatively less reducing potential following the substitution of the axial Cl– ligand with solvent water. Dominant Co­(I)-centric H2 production reactivity was observed in further cathodic potential. Incorporation of dynamic peripheral basic functionalities enhanced H+ trafficking around the cobaloxime core to significantly improve (∼2.0–9.5 times) Co­(I)-centric H2 production reactivity. Complementary NMR and electrochemical results suggest that formation of an intricately interactive water-assisted proton relay neighboring the metal core is the prime reason for this improved activity. Additionally, these peripheral basic functionalities, blended with proton relay, provided an alternative protonation site during the catalysis to induce unprecedented H2 production for cobaloximes under acidic aqueous conditions (pH < 5). Thus, this work provides a prime example of catalytic upgradation of an already existing, moderately active synthetic complex core by encompassing it with precisely positioned enzyme-inspired basic functionalities and water molecules.

The present study aimed to evaluate the protective effect of maslinic acid (MA) on body weight, heart weight, lipids, lipoproteins, lipid peroxidation (LPO), cardiac marker enzymes, and paraoxonase (PON) in normal control and isoproterenol (ISO)-induced myocardial infarcted albino Wistar rats. After treatment with MA (15 mg/kg) for 7 days, myocardial infarction was induced by subcutaneous injection of ISO (85 mg/kg) for two consecutive days. ISO caused a considerable decrease in body weight and increased the heart weight. The concentrations of total cholesterol, triglycerides, very low-density lipoprotein-cholesterol, and low-density lipoprotein-cholesterol were higher, whereas that of high-density lipoprotein-cholesterol was lower, in the serum of ISO-administered rats. The activities of the cardiac marker enzymes creatine kinase, alanine transaminase, aspartate transaminase, and γ-glutamyl transferase and levels of malondialdehyde were elevated in the serum of ISO-treated rats. ISO-administered rats also exhibited a decline in the activity of PON. Pretreatment of rats with MA reduced the effects of ISO on all parameters tested. This is the first report of the protective effect of MA on ISO-induced cardiotoxicity and of an association between PON status and MA supplementation. The observed cardioprotective effects may be due to the antihyperlipidemic potential of MA, inhibition of LPO, and antioxidant activity.

Human Tousled-like kinases (TLKs) are highly conserved serine/threonine protein kinases responsible for cell proliferation, DNA repair, and genome surveillance. Their possible involvement in cancer via efficient DNA repair mechanisms have made them clinically relevant molecular targets for anticancer therapy. Innovative approaches in chemical biology have played a key role in validating the importance of kinases as molecular targets. However, the detailed understanding of the protein structure and the mechanisms of protein–drug interaction through biochemical and biophysical techniques demands a method for the production of an active protein of exceptional stability and purity on a large scale. We have designed a bacterial expression system to express and purify biologically active, wild-type Human Tousled-like Kinase 1B (hTLK1B) by co-expression with the protein phosphatase from bacteriophage λ. We have obtained remarkably high amounts of the soluble and homogeneously dephosphorylated form of biologically active hTLK1B with our unique, custom-built vector design strategy. The recombinant hTLK1B can be used for the structural studies and may further facilitate the development of new TLK inhibitors for anti-cancer therapy using a structure-based drug design approach.

Helicobacter pylori (H. pylori), the major cause of several gastric disorders has been recognied as a type I carcinogen. By virtue of resistance developed by H. pylori strains, currently used antibiotic based treatments rather demonstrate high failure rates. Hence, there is an emerging need for identification of new targets to treat H. pylori infection. Inosine-5′-monophosphate dehydrogenase (IMPDH) has been studied as a potential target to treat H. pylori infection. Here, a detailed enzyme kinetic study of recombinant expressed H. pylori inosine-5′-monophosphate dehydrogenase (HpIMPDH) is presented. A new in-house synthesized indole-based scaffold is identified as an inhibitor for HpIMPDH. These indole-based compounds showed non-competitive inhibition against IMP and NAD+ whereas the benzimidazole compounds were found be uncompetitive inhibitors. The new indole scaffold ensures specificity due to its high selectivity for bacterial IMPDH over human IMPDH II. Our work aims to overcome the drawback of existing inhibitors by introducing new indole scaffold for targeting bacterial IMPDH.

No abstract