Identification of novel anthrax lethal factor inhibitors generated by combinatorial Pictet-Spengler reaction followed by screening in situ
Identification of novel anthrax lethal factor inhibitors generated by combinatorial Pictet-Spengler reaction followed by screening in situ
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DOI：
10.1002/cbic.200500009
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发表时间：
2005-06-01
期刊：
影响因子：
3.2
通讯作者：
Wong, CH
中科院分区：
文献类型：
--
作者：
Numa, MMD;Lee, LV;Wong, CH
1002 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim DOI: 10.1002/cbic。[200500009]巨噬细胞[9]细胞膜外表面的研究。细胞膜表面也存在一种类似于呋喃蛋白的蛋白酶，它通过切割PA的n端20kd片段来激活PA活化的PA分子寡聚形成具有通道状结构的七聚体（图1a），然后能够与LF和EF结合（图1B）。由七聚体PA、LF和EF组成的集合通过内吞作用被吸收到细胞中（图1c）pH值的变化会向PA发出信号，介导LF和EF从胞吞囊泡向胞浆的逃逸（图1d）。一旦进入细胞质（图1e）， EF的存在就会引发cAMP浓度的增加，从而导致水流入细胞，从而引起水肿然后，LF切割丝裂原活化蛋白激酶（MAPKK）的n端片段[12,13,14]，这是其唯一已知的天然底物，引发一系列事件，导致宿主细胞凋亡。[15,16]吸入性炭疽是最严重的感染形式。它迅速发展为全身性疾病，除非在早期阶段用抗生素治疗，否则几乎没有生存的机会一旦宿主体内产生的LTx数量达到临界阈值，抗生素就会失效，感染就无法阻止。皮肤和消化道感染通常是局部的，但如果不及时治疗，可以传播，造成与吸入性炭疽相同的后果。若想在炭疽芽孢杆菌感染的晚期得到有效的治疗，就需要阻断LTx的活性，特别是阻断LF的活性。因此，识别抗LF的有效抑制剂和了解其不同寻常的作用模式是主要的兴趣，并已成为几项研究的焦点。据报道，多种结构可以抑制LF的活性[18-23]，并延长细胞培养物或动物模型的存活时间。
1002 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim DOI: 10.1002/cbic. 200500009 ChemBioChem 2005, 6, 1002–1006 outer surface of the macrophage [9] cell membrane. There a furin-like protease, which is also present on the surface of the cell membrane, activates PA by cleaving its N-terminal 20 kD fragment.[10] The activated PA molecules oligomerize to form a heptamer with a channel-like structure (Figure1A), which is then able to bind to LF and EF (Figure 1B). The ensemble composed of heptameric PA, LF, and EF is absorbed into the cell by endocytosis (Figure 1 C).[4] A pH change then signals PA to mediate the escape of LF and EF from the endocytosis vesicle to the cytosol (Figure1D). Once inside the cytosol (Figure1E), the presence of EF triggers an increase in the cAMP concentration, which leads to a flow of water into the cell and thus causes edema.[11] LF then cleaves the N-terminal fragment of mitogen-activated protein kinase kinase (MAPKK),[12, 13, 14] its only known natural substrate, which triggers a cascade of events that lead to the apoptosis of the host cell.[15, 16] Inhalation anthrax is the most severe form of infection. It evolves rapidly to be systemic and leaves almost no chance of survival unless treated in the very early stage with antibiotics.[17] Antibiotics become ineffective and the infection unstoppable once the quantity of LTx produced in the host body reaches a critical threshold. Cutaneous and digestive infections are usually localized but can spread with the same consequences as inhalation anthrax, if left untreated. An efficient treatment of the Bacillus anthracis infection in the late stage requires blocking the activity of LTx, and more specifically that of LF.The identification of potent inhibitors against LF and the understanding of its unusual mode of action is therefore of primary interest and it has been the focus of several studies. Various structures have been reported to inhibit the activity of LF [18–23] and to prolong the survival of cell cultures or animal models.