Michael acceptor-containing coenzyme A analogues as inhibitors of the atypical coenzyme A disulfide reductase from Staphylococcus aureus.
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.
van der Westhuyzen
Renier
R
Department of Biochemistry, Stellenbosch University, Private bag X1, Matieland 7602, South Africa.
Strauss
Erick
E
D003065:Coenzyme A / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D007700:Kinetics; D009247:NADH, NADPH Oxidoreductases / Q000037:antagonists & inhibitors*; D013211:Staphylococcus aureus / Q000201:enzymology*
D004791:Enzyme Inhibitors; D009247:NADH, NADPH Oxidoreductases; C519574:coenzyme A disulfide reductase, Staphylococcus aureus; D003065:Coenzyme A