Bacterial thioredoxin reductase inhibitors and methods for use thereof

US8592468B2 · kind B2 · utility

Assignee

• Thioredoxin Systems AB · SE

Inventors

• Arne Holmgren · Stockholm, SE
• Jun Lu · East Longmeadow, US
• Alexios Vlamis-Gardikas · Stockholm, SE
• Rong Zhao · Stockholm, SE
• Karuppasamy Kandasamy · Stockholm, SE
• Lars Engman · Uppsala, SE
• Lars Engstrand · Stockholm, SE
• Sven Hoffner · Stockholm, SE

Key dates

• Filing date: Mar 23, 2011
• Grant date: Nov 26, 2013
• Expiry date: Mar 23, 2031

Classification

• Technology area (CPC Y): Emerging Cross-Sectional Technologies
• CPC primary: Y02A50/30
• WIPO field: Pharmaceuticals
• WIPO sector: Chemistry

Abstract

The mechanism of action of Ebselen differentiates between bacterial and mammalian thioredoxin reductase (TrxR). It displays fast oxidation of mammalian Trx and via the NADPH-TrxR catalyzed turnover of ebselen selenol with hydrogen peroxide, and therefore are mammalian antioxidants. Ebselen, and its diselenide, are strong competitive inhibitors of E. coli TrxR with Ki of 0.14 μM and 0.46 μM, respectively. E. coli mutants lacking glutathione reductase or glutathione were much more sensitive to inhibition by ebselen. Since either glutaredoxin or thioredoxin systems are electron donors to ribonucleotide reductase, ebselen targets primarily glutathione and glutaredoxin-negative bacteria, a class which includes major pathogens. Ebselen, and similar compounds are therefore useful as antibacterial agents, even for multiresistant strains. Two major pathogenic bacteria, which previously had not been known to be sensitive to ebselen, Mycobacterium tuberculosis (tuberculosis) and Helicobacter pylori (stomach ulcer and cancer), were shown to be excellent targets. Helicobacter pylori was also sensitive to ebsulfur.