Development and binding characteristics of phosphonate inhibitors of SplA protease from Staphylococcus aureus |
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Authors: | Ewa Burchacka Michal Zdzalik Justyna‐Stec Niemczyk Katarzyna Pustelny Grzegorz Popowicz Benedykt Wladyka Adam Dubin Jan Potempa Marcin Sienczyk Grzegorz Dubin Jozef Oleksyszyn |
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Institution: | 1. Division of Medicinal Chemistry and Microbiology, Faculty of Chemistry, Wroclaw University of Technology, , Wroclaw, Poland;2. Department of Microbiology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, , Krakow, Poland;3. Department of Analytical Biochemistry, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, , Krakow, Poland;4. Max‐Planck Institute for Biochemistry, , Martinsried, Germany;5. Malopolska Centre of Biotechnology, , Krakow, Poland |
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Abstract: | 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-PheP-(OC6H4−4-SO2CH3)2 and Suc-Val-Pro-PheP-(OC6H5)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. |
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Keywords: | Staphylococcus aureus SplA protease protease inhibitor α ‐aminoalkylphosphonate |
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