title: Development and binding characteristics of phosphonate inhibitors of SplA protease from Staphylococcus aureus.
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-Phe(P) -(OC6 H4 -4-SO2 CH3 )2 and Suc-Val-Pro-Phe(P) -(OC6 H5 )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.
authors.affiliation: Division of Medicinal Chemistry and Microbiology, Faculty of Chemistry, Wroclaw University of Technology, Wroclaw, Poland.
authors.forename: Ewa
authors.initials: E
authors.lastname: Burchacka
authors.forename: Michal
authors.initials: M
authors.lastname: Zdzalik
authors.forename: Justyna-Stec
authors.initials: JS
authors.lastname: Niemczyk
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Pustelny
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Popowicz
authors.forename: Benedykt
authors.initials: B
authors.lastname: Wladyka
authors.forename: Adam
authors.initials: A
authors.lastname: Dubin
authors.forename: Jan
authors.initials: J
authors.lastname: Potempa
authors.forename: Marcin
authors.initials: M
authors.lastname: Sienczyk
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Dubin
authors.forename: Jozef
authors.initials: J
authors.lastname: Oleksyszyn
mesh_terms: D001426:Bacterial Proteins / Q000737:chemistry*; D018360:Crystallography, X-Ray; D006801:Humans; D007700:Kinetics; D063065:Organophosphonates / Q000737:chemistry / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects; D057057:Serine Proteases / Q000737:chemistry*; D015842:Serine Proteinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D013211:Staphylococcus aureus / Q000201:enzymology* / Q000472:pathogenicity
chemical_list: D001426:Bacterial Proteins; D063065:Organophosphonates; D015842:Serine Proteinase Inhibitors; D057057:Serine Proteases
keywords: SplA protease; Staphylococcus aureus; protease inhibitor; α-aminoalkylphosphonate