Zafirlukast is a broad‐spectrum thiol isomerase inhibitor that inhibits thrombosis without altering bleeding times

Abstract

Background and Purpose: Multiple members of the thiol isomerase (TI) family of enzymes are present in and released by platelets. Inhibition of these enzymes results in diminished platelet responses, aggregation, adhesion and thrombus formation.Recently, the therapeutic potential of TI inhibition has been recognised and drugdevelopment technologies were used to identify selective small molecule inhibitors.To date, few pan-TI inhibitors have been characterised and the most studied, bacitracin, is known to be nephrotoxic, which prohibits its systemic therapeutic usage.Experimental Approach: We therefore sought to identify novel broad-spectrum inhibitors of these enzymes and test their effects in vivo. A total of 3,641 compounds were screened for inhibitory effects on the redox activity of ERp5, protein disulphide isomerase (PDI), ERp57, ERp72 and thioredoxin in an insulin turbidity assay. Of the lead compounds identified, zafirlukast was selected for further investigation.

Pathophysiological roles of cell surface and extracellular protein disulfide isomerase and their molecular mechanisms

“…Zafirlukast inhibits both in vitro platelet activation and in vivo thrombus formation without prolonging bleeding time in mice (Holbrook et al, 2020).…”

“…Notably, zafirlukast, a cysteinyl LT receptor antagonist used in the treatment of asthma, has been recently reported as a broad‐spectrum inhibitor for thiol isomerases including PDI, ERp57, ERp5 and ERp72. Zafirlukast inhibits both in vitro platelet activation and in vivo thrombus formation without prolonging bleeding time in mice (Holbrook et al, 2020).…”

In Vitro Activity of Peptide Antibiotics in Combination With Other Antimicrobials on Extensively Drug-Resistant Acinetobacter baumannii in the Planktonic and Biofilm Cell

“…Our results were consistent with the study by Park et al (2019) , which showed that the combination of polymyxin and rifampicin has been used successfully against polymyxin-resistant A. baumannii pneumonia. Bacitracin is a peptide antibiotic, it’s parenteral administration is highly restricted due to its nephrotoxicity, which prohibits its systemic therapeutic usage ( Holbrook et al, 2021 ). Therefore, bacitracin is commonly used in combination with polymyxin and neomycin as triple antibiotic ointment for the topical treatment of wound infections ( Sierra et al, 2017 ).…”

Thiol Isomerases Orchestrate Thrombosis and Hemostasis

“…Finally, we have recently shown that the cysteinyl LT receptor antagonist zafirlukast is a pan inhibitor of thiol isomerases, decreasing the reductase activity of PDI, ERp5, ERp57, ERp72 and TRX at micromolar concentrations 138 . Similar concentrations of zafirlukast were able to inhibit platelet aggregation, activation, calcium mobilization and in vivo thrombosis with no effect on bleeding time 138 . Therefore, there are currently few small molecule inhibitors of PDI and other thiol isomerases with well-described effects in thrombosis and haemostasis.…”