Phosphonic analogues of glutamic acid as irreversible inhibitors of Staphylococcus aureus endoproteinase GluC: an efficient synthesis and inhibition of the human IgG degradation

Bioorg Med Chem Lett. 2013 Mar 1;23(5):1412-5. doi: 10.1016/j.bmcl.2012.12.074. Epub 2013 Jan 5.

Abstract

Endoproteinase GluC (V8 protease) is one of many virulence factors released by the Staphylococcus aureus species in vivo. The V8 protease is able to hydrolyze some serpins and all classes of mammalian immunoglobulins. The application of specific and potent inhibitors of V8 protease may lead to the development of new antibacterial agents. Herein, we present the synthesis and the inhibitory properties of novel peptidyl derivatives of a phosphonic glutamic acid analogue. One of the compounds Boc-Phe-Leu-Glu(P)(OC(6)H(4))(2) displayed an apparent second-order inhibition rate value of 8540 M(-1)s(-1). The Boc-Phe-Leu-Glu(P)(OC(6)H(4))(2) compound with the highest inhibitory potency showed the ability to prevent V8-mediated human IgG proteolysis in vitro.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Glutamic Acid / analogs & derivatives*
  • Glutamic Acid / pharmacology
  • Glutamine / analogs & derivatives*
  • Glutamine / pharmacology
  • Humans
  • Immunoglobulin G / chemistry
  • Immunoglobulin G / metabolism*
  • Serine Endopeptidases / metabolism*
  • Serine Proteinase Inhibitors / chemistry*
  • Serine Proteinase Inhibitors / pharmacology*
  • Staphylococcus aureus / drug effects
  • Staphylococcus aureus / enzymology*

Substances

  • Immunoglobulin G
  • Serine Proteinase Inhibitors
  • Glutamine
  • Glutamic Acid
  • Serine Endopeptidases
  • glutamyl endopeptidase