The development of first Staphylococcus aureus SplB protease inhibitors: phosphonic analogues of glutamine

Bioorg Med Chem Lett. 2012 Sep 1;22(17):5574-8. doi: 10.1016/j.bmcl.2012.07.011. Epub 2012 Jul 13.

Abstract

Produced by Staphylococcus aureus, SplB belongs to the chymotrypsin-like serine protease family. Since the biological role of SplB protease is unknown, the design and application of its specific inhibitors may help to reveal the function of this enzyme. Until now no SplB inhibitors have been reported. Herein, we present the design and synthesis of novel α-aminophosphonic analogues of glutamine, as well as their peptidyl derivatives. The inhibitory effects of these compounds towards the newly discovered SplB serine protease from S. aureus are characterized. We have also investigated the influence of aromatic ester substituents on inhibitory potency towards SplB. One of the compounds-Cbz-Glu-Leu-Gln(P)(OC(6)H(4)-4-O-CH(3))(2)-displayed an apparent second-order inhibition rate value of 1400 M(-1)s(-1).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Glutamine / analogs & derivatives*
  • Glutamine / pharmacology*
  • Humans
  • Serine Proteases / metabolism
  • Serine Proteinase Inhibitors / chemistry*
  • Serine Proteinase Inhibitors / pharmacology*
  • Staphylococcal Infections / drug therapy
  • Staphylococcal Infections / microbiology
  • Staphylococcus aureus / drug effects
  • Staphylococcus aureus / enzymology*

Substances

  • Serine Proteinase Inhibitors
  • Glutamine
  • Serine Proteases