School of Pharmacy, Queens University Belfast, Medical Biology Centre, 97 Lisburn Road, Belfast BT9 7BL, UK.
Biochimie. 2011 Oct;93(10):1824-7. doi: 10.1016/j.biochi.2011.06.030. Epub 2011 Jul 6.
In this study we report for the first time the comprehensive inhibitor profiling of the Proteus mirabilis metalloprotease virulence factor ZapA (mirabilysin) using a 160 compound focused library of N-alpha mercaptoamide dipeptides, in order to map the S(1)(') and S(2)(') binding site preferences of this important enzyme. This study has revealed a preference for the aromatic residues tyrosine and tryptophan in P(1)(') and aliphatic residues in P(2)('). From this library, six compounds were identified which exhibited sub- to low-micromolar K(i) values. The most potent inactivator, SH-CO(2)-Y-V-NH(2) was capable of preventing ZapA-mediated hydrolysis of heat-denatured IgA, indicating that these inhibitors may be capable of protecting host proteins against ZapA during colonisation and infection.
在这项研究中，我们首次报道了使用 160 种化合物的 N-α 巯基酰胺二肽聚焦文库，对变形杆菌属金属蛋白酶毒力因子 ZapA（奇异变形菌蛋白酶）进行全面抑制剂分析，以绘制这种重要酶的 S1(')和 S2(')结合位点偏好性。这项研究揭示了 P1(')中对芳香族残基酪氨酸和色氨酸以及 P2(')中对脂族残基的偏好性。从这个文库中，鉴定出了六种具有亚微摩尔至低微摩尔 K(i)值的化合物。最有效的失活剂 SH-CO2-Y-V-NH2 能够阻止 ZapA 介导的热变性 IgA 的水解，表明这些抑制剂在定植和感染期间可能能够保护宿主蛋白免受 ZapA 的侵害。
