Phosphonic analogues of glutamic acid as irreversible inhibitors of Staphylococcus aureus endoproteinase GluC: an efficient synthesis and inhibition of the human IgG degradation.
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.
Division of Medicinal Chemistry and Microbiology, Faculty of Chemistry, Wrocław University of Technology, Wybrzeże Wyspiańskiego 27, 50-370 Wrocław, Poland.
Ewa
E
Burchacka
Marcin
M
Skoreński
Marcin
M
Sieńczyk
Józef
J
Oleksyszyn
D018698:Glutamic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D005973:Glutamine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D007074:Immunoglobulin G / Q000737:chemistry / Q000378:metabolism*; D012697:Serine Endopeptidases / Q000378:metabolism*; D015842:Serine Proteinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D013211:Staphylococcus aureus / Q000187:drug effects / Q000201:enzymology*
D007074:Immunoglobulin G; D015842:Serine Proteinase Inhibitors; D005973:Glutamine; D018698:Glutamic Acid; D012697:Serine Endopeptidases; C028344:glutamyl endopeptidase