Michael Acceptor-Containing Coenzyme A Analogues As Inhibitors of the Atypical Coenzyme A Disulfide Reductase from Staphylococcus aureus

• Published in: Journal of the American Chemical Society Vol. 132; no. 37; pp. 12853 - 12855
• Main Authors: van der Westhuyzen, Renier, Strauss, Erick
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 22.09.2010; Amer Chemical Soc
• Subjects: Chemistry; Chemistry, Multidisciplinary; Coenzyme A - chemical synthesis; Coenzyme A - chemistry; Coenzyme A - pharmacology; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Kinetics; NADH, NADPH Oxidoreductases - antagonists & inhibitors; Physical Sciences; Science & Technology; Staphylococcus aureus - enzymology; EXPRESSION; ENZYME; CYSTEINE PROTEASE INHIBITORS
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/ja106204m

Coenzyme A (CoA) analogues containing α,β-unsaturated ester, ketone, and sulfone moieties were prepared by chemo-enzymatic synthesis as inhibitors of coenzyme A disulfide reductase (CoADR), a proven and as yet unexploited drug target in Staphylococcus aureus. Among these Michael acceptor-containing CoA analogues, which were designed to target CoADR’s single essential active site cysteine for conjugate addition, a phenyl vinyl sulfone-containing analogue showed the most potent inhibition with a competitive K i of ∼40 nM, and time-dependent inactivation with a second-order rate of inactivation constant of ∼40 000 s−1·M−1. Our results suggest that electrophilic substrate analogues should be considered as potential inhibitors of other medicinally relevant disulfide reductase enzymes.