Activators of Cylindrical Proteases as Antimicrobials: Identification and Development of Small Molecule Activators of CIpP Protease
Activators of Cylindrical Proteases as Antimicrobials: Identification and Development of Small Molecule Activators of CIpP Protease
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DOI：
10.1016/j.chembiol.2011.07.023
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发表时间：
2011-09-23
影响因子：
--
通讯作者：
Houry, Walid A.
中科院分区：
文献类型：
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作者：
Leung, Elisa;Datti, Alessandro;Houry, Walid A.
CIPP是一种圆柱形丝氨酸蛋白酶，其降解蛋白质的能力受去折叠酶ATP依赖的伴侣调节。CIPP本身只能降解小肽。在这里，我们使用CIPP作为高通量筛选化合物的靶点，这些化合物激活了蛋白酶并允许它降解更大的蛋白质，从而消除了ATP依赖的伴侣蛋白产生的特异性。我们的筛选结果是五个不同的化合物，我们指定它们为自划分蛋白1至5(ACP1至5)的激活剂。这些化合物具有稳定CIPP双环结构的作用。ACP1的化学结构被认为具有类药物特性，并进一步优化，以给出具有杀菌活性的类似物。因此，ACPs代表了能够激活CIPP的一类化合物，可以开发为潜在的新型抗生素。
CIpP is a cylindrical serine protease whose ability to degrade proteins is regulated by the unfoldase ATP-dependent chaperones. CIpP on its own can only degrade small peptides. Here, we used CIpP as a target in a high-throughput screen for compounds, which activate the protease and allow it to degrade larger proteins, hence, abolishing the specificity arising from the ATP-dependent chaperones. Our screen resulted in five distinct compounds, which we designate as Activators of Self-Compartmentalizing Proteases 1 to 5 (ACP1 to 5). The compounds are found to stabilize the CIpP double-ring structure. The ACP1 chemical structure was considered to have drug-like characteristics and was further optimized to give analogs with bactericidal activity. Hence, the ACPs represent classes of compounds that can activate CIpP and that can be developed as potential novel antibiotics.