The development of first Staphylococcus aureus SplB protease inhibitors: Phosphonic analogues of glutamine

Produced by Staphylococcus aureus, SplB belongs to the chymotrypsin-like serine protease family. Since the biological role of SplB protease is unknown, the design and application of its specific inhibitors may help to reveal the function of this enzyme. Until now no SplB inhibitors have been reported. Herein, we present the design and synthesis of novel α-aminophosphonic analogues of glutamine, as well as their peptidyl derivatives. The inhibitory effects of these compounds towards the newly discovered SplB serine protease from S. aureus are characterized. We have also investigated the influence of aromatic ester substituents on inhibitory potency towards SplB. One of the compounds-Cbz-Glu-Leu-Gln(P)(OC(6)H(4)-4-O-CH(3))(2)-displayed an apparent second-order inhibition rate value of 1400M(-1)s(-1).     

Development and binding characteristics of phosphonate inhibitors of SplA protease from Staphylococcus aureus

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-(OC₆H₄−4-SO₂CH₃)₂ and Suc-Val-Pro-Phe^P-(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.     

Stomatal Responses of Bean (Phaseolus Vulgaris L.) Leaves to Changing Irradiance,Air Humidity,and Water Potential of Root Medium

Stomatal responses of attached bean (Phaseolus vulgaris L.) leaves to changing spectral composition ("white" - WL., blue - BL, or red - RL radiation), air humidity (100 % or about 4 % RH), and water potential of the root medium (close to 0 or −1.2 MPa) were determined by air flow porometer. Opening of stomata always increased under BL and decreased under RL. In response to decline in air humidity, leaf conductance showed transient increase before it reached lowered steady state. BL enhanced and RL diminished this response. This revised version was published online in June 2006 with corrections to the Cover Date.     

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(OC₆H₄)₂ displayed an apparent second-order inhibition rate value of 8540 M^?1 s^?1. The Boc-Phe-Leu-Glu^P(OC₆H₄)₂ compound with the highest inhibitory potency showed the ability to prevent V8-mediated human IgG proteolysis in vitro.