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Development and binding characteristics of phosphonate inhibitors of SplA protease from Staphylococcus aureus
Author(s) -
Burchacka Ewa,
Zdzalik Michal,
Niemczyk JustynaStec,
Pustelny Katarzyna,
Popowicz Grzegorz,
Wladyka Benedykt,
Dubin Adam,
Potempa Jan,
Sienczyk Marcin,
Dubin Grzegorz,
Oleksyszyn Jozef
Publication year - 2014
Publication title -
protein science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.353
H-Index - 175
eISSN - 1469-896X
pISSN - 0961-8368
DOI - 10.1002/pro.2403
Subject(s) - staphylococcus aureus , phosphonate , protease , microbiology and biotechnology , chemistry , enzyme , biochemistry , biology , bacteria , genetics
Staphylococcus aureus is responsible for a variety of human infections, including life‐threatening, systemic conditions. Secreted proteome, including a range of proteases, constitutes the major virulence factor of the bacterium. However, the functions of individual enzymes, in particular SplA protease, remain poorly characterized. Here, we report development of specific inhibitors of SplA protease. The design, synthesis, and activity of a series of α‐aminoalkylphosphonate diaryl esters and their peptidyl derivatives are described. Potent inhibitors of SplA are reported, which may facilitate future investigation of physiological function of the protease. The binding modes of the high‐affinity compounds Cbz‐Phe P ‐(OC 6 H 4 −4‐SO 2 CH 3 ) 2 and Suc‐Val‐Pro‐Phe P ‐(OC 6 H 5 ) 2 are revealed by high‐resolution crystal structures of complexes with the protease. Surprisingly, the binding mode of both compounds deviates from previously characterized canonical interaction of α‐aminoalkylphosphonate peptidyl derivatives and family S1 serine proteases.