Lansoprazole inhibits the cysteine protease legumain by binding to the active site.

Article Details

Citation
Copy to clipboard

Bosnjak T, Solberg R, Hemati PD, Jafari A, Kassem M, Johansen HT

Lansoprazole inhibits the cysteine protease legumain by binding to the active site.

Basic Clin Pharmacol Toxicol. 2019 Mar 27. doi: 10.1111/bcpt.13230.

PubMed ID
30916878 [ View in PubMed
]
Abstract

Proton pump inhibitors (PPIs) are prodrugs used in the treatment of peptic ulcer diseases. Once activated by acidic pH, the PPIs subsequently inhibit the secretion of gastric acid by covalently forming disulphide bonds with the SH groups of the parietal proton pump, i.e. the H(+) /K(+) -ATP-ase. Long-term use of PPIs has been associated with numerous adverse effects, including bone fractures. Considering the mechanism of activation, PPIs could also be active in acidic micro-environments such as in lysosomes, tumours and bone resorption sites. We hypothesized that the SH group in the active site of cysteine proteases could be susceptible for inhibition by PPIs. In this study, the inhibition by lansoprazole was shown on the cysteine proteases legumain and cathepsin B by incubating purified proteases or cell lysates with lansoprazole at different concentrations and pH conditions. The mechanism of legumain inhibition was shown to be a direct interaction of lansoprazole with the SH group in the active site, and thus blocking binding of the legumain-selective activity-based probe MP-L01. Lansoprazole was also shown to inhibit both legumain and cathepsin B in various cell models like HEK293, M38L and RAW264.7, but not in human bone marrow-derived skeletal (mesenchymal) stem cells (hBMSC-TERT). During hBMSC-TERT differentiation to osteoblasts, lansoprazole inhibited legumain secretion, alkaline phosphatase activity, but had no effects on in vitro mineralization capacity. In conclusion, lansoprazole acts as a direct covalent inhibitor of cysteine proteases via disulphide bonds with the SH group in the protease active site. Such inhibition of cysteine proteases could explain some of the off-target effects of PPIs. This article is protected by copyright. All rights reserved.

DrugBank Data that Cites this Article

Drugs