Inhibitors of the Metalloproteinase Anthrax Lethal Factor.
Inhibitors of the Metalloproteinase Anthrax Lethal Factor.
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DOI：
10.2174/1568026616666160413135732
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发表时间：
2016
影响因子：
3.4
通讯作者：
Turk BE
中科院分区：
文献类型：
--
作者：
Goldberg AB;Turk BE
炭疽芽孢杆菌是一种杆状、形成孢子的革兰氏阳性细菌，是炭疽病的病原体。炭疽芽孢杆菌的毒力部分归因于两种分泌的二分蛋白毒素，它们在宿主细胞内作用，破坏对宿主防御感染至关重要的信号通路。这些毒素也可能直接导致晚期感染的死亡。锌依赖性金属蛋白酶炭疽致死因子 (LF) 是这些蛋白质毒素之一的关键成分，也是开发抑制剂以生产炭疽疗法的主要目标。在这里，我们描述了最近为识别特异性和有效的 LF 抑制剂所做的努力。带有锌结合基团的肽底物类似物的衍生化产生了有效且特异性的 LF 抑制剂，而 LF 抑制剂复合物的 X 射线晶体学提供了对高亲和力结合所需特征的深入了解。新型抑制剂支架已通过多种方法确定，包括基于片段的药物发现、虚拟筛选和不同化合物库的高通量筛选。最后，发现 LF 抑制剂的努力导致了新筛选策略的开发，例如使用全长蛋白质作为底物，这可能对其他蛋白酶也有用。总的来说，这些努力已经产生了一系列化学和机械上多样化的分子，能够在体外和细胞内以及炭疽感染的动物模型中抑制 LF 活性。
Bacillus anthracis, a rod shaped, spore forming, gram positive bacteria, is the etiological agent of anthrax. B. anthracis virulence is partly attributable to two secreted bipartite protein toxins, which act inside host cells to disrupt signaling pathways important for host defense against infection. These toxins may also directly contribute to mortality in late stage infection. The zinc-dependent metalloproteinase anthrax lethal factor (LF) is a critical component of one of these protein toxins and a prime target for inhibitor development to produce anthrax therapeutics. Here, we describe recent efforts to identify specific and potent LF inhibitors. Derivatization of peptide substrate analogs bearing zinc-binding groups has produced potent and specific LF inhibitors, and X-ray crystallography of LF-inhibitor complexes has provided insight into features required for high affinity binding. Novel inhibitor scaffolds have been identified through several approaches, including fragment-based drug discovery, virtual screening, and high-throughput screening of diverse compound libraries. Lastly, efforts to discover LF inhibitors have led to the development of new screening strategies, such as the use of full-length proteins as substrates, that may prove useful for other proteases as well. Overall, these efforts have led to a collection of chemically and mechanistically diverse molecules capable of inhibiting LF activity in vitro and in cells, as well as in animal models of anthrax infection.
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影响因子：
5.6
作者：
Chiu TL;Solberg J;Patil S;Geders TW;Zhang X;Rangarajan S;Francis R;Finzel BC;Walters MA;Hook DJ;Amin EA
通讯作者：
Amin EA
影响因子：
2.7
作者：
Kim, Seongjin;Jiao, Guan-Sheng;Moayeri, Mahtab;Crown, Devorah;Cregar-Hernandez, Lynne;McKasson, Linda;Margosiak, Stephen A.;Leppla, Stephen H.;Johnson, Alan T.
通讯作者：
Johnson, Alan T.
影响因子：
4.1
作者：
Bardwell, AJ;Abdollahi, M;Bardwell, L
通讯作者：
Bardwell, L
影响因子：
3.2
作者：
Goehler, Anna-Katharina;Staab, Ariane;Jahreis, Knut
通讯作者：
Jahreis, Knut
影响因子：
3.4
作者：
Agrawal, Arpita;Johnson, Sherida L.;Jacobsen, Jennifer A.;Miller, Melissa T.;Chen, Li-Hsing;Pellecchia, Maurizio;Cohen, Seth M.
通讯作者：
Cohen, Seth M.