Structure, mechanism, and inhibition of aspergillus fumigatus thioredoxin reductase
| Autor: | Sarah E. Kidd, Bryan R. Coad, Andrew C Marshall, John B. Bruning, Peter Hoffmann, Georgia Arentz, Stephanie J. Lamont-Friedrich |
|---|---|
| Přispěvatelé: | Marshall, Andrew C, Kidd, Sarah E, Lamont-Friedrich, Stephanie J, Arentz, Georgia, Hoffmann, Peter, Coad, Bryan R, Bruning, John B |
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Pharmacology
chemistry.chemical_classification 0303 health sciences Aspergillus biology Chemistry Ebselen In silico Thioredoxin reductase 030302 biochemistry & molecular biology biology.organism_classification In vitro Aspergillus fumigatus 03 medical and health sciences chemistry.chemical_compound Infectious Diseases Biochemistry Oxidoreductase Pharmacology (medical) 030304 developmental biology Cysteine |
| Popis: | Aspergillus fumigatus infections are associated with high mortality rates and high treatment costs. Limited available antifungals and increasing antifungal resistance highlight an urgent need for new antifungals. Thioredoxin reductase (TrxR) is essential for maintaining redox homeostasis and presents as a promising target for novel antifungals. We show that ebselen [2-phenyl-1,2-benzoselenazol-3(2H)-one] is an inhibitor of A. fumigatus TrxR (K i 0.22 M) and inhibits growth of Aspergillus spp., with in vitro MIC values of 16 to 64 g/ml. Mass spectrometry analysis demonstrates that ebselen interacts covalently with a catalytic cysteine of TrxR, Cys148. We also present the X-ray crystal structure of A. fumigatus TrxR and use in silico modeling of the enzyme-inhibitor complex to outline key molecular interactions. This provides a scaffold for future design of potent and selective antifungal drugs that target TrxR, improving the potency of ebselen toward inhbition of A. fumigatus growth Refereed/Peer-reviewed |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|