Rational Design of Selective and Bioactive Inhibitors of the Mycobacterium tuberculosis Proteasome.
Rational Design of Selective and Bioactive Inhibitors of the Mycobacterium tuberculosis Proteasome.
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DOI：
10.1021/acsinfecdis.6b00172
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发表时间：
2017-02-10
影响因子：
5.3
通讯作者：
Sello JK
中科院分区：
文献类型：
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作者：
Totaro KA;Barthelme D;Simpson PT;Jiang X;Lin G;Nathan CF;Sauer RT;Sello JK
M.结核病（Mtb）是一个有希望的、但非常规的药物靶点。这种多聚体肽酶不是必需的，但通过与宿主免疫应答期间产生的一氧化氮（和/或相关的活性氮中间体）反应来降解已经受损和有毒的蛋白质。蛋白酶体抑制剂可以使Mtb对免疫系统敏感，但只有在它们不抑制人体中必需的20S对应物的情况下，它们才是治疗上可行的。我们设计和合成的Mtb 20 S的选择性抑制剂的基础上，其独特的底物的偏好和结构的底物模拟共价抑制剂的真核蛋白酶体被称为双黄嘌呤。与亲本黄芩素不同，所设计的类似物微弱地抑制人20S（Hs 20S）蛋白酶体，并且优先抑制Mtb 20S超过人对应物多达74倍。此外，它们可以穿透分枝杆菌细胞包膜并使Mtb对一氧化氮介导的应激敏感。重要的是，它们在体外不抑制人类细胞系的生长，因此可能是结核病药物开发的起点。
The 20S core particle of the proteasome in M. tuberculosis (Mtb) is a promising, yet unconventional drug target. This multimeric peptidase is not essential, yet degrades proteins that have become damaged and toxic via reactions with nitric oxide (and/or the associated reactive nitrogen intermediates) produced during the host immune response. Proteasome inhibitors could render Mtb susceptible to the immune system, but they would only be therapeutically viable if they do not inhibit the essential 20S counterpart in humans. We designed and synthesized selective inhibitors of the Mtb 20S based on both its unique substrate preferences and the structures of substrate-mimicking covalent inhibitors of eukaryotic proteasomes called syringolins. Unlike the parent syringolins, the designed analogs weakly inhibit the human 20S (Hs 20S) proteasome and preferentially inhibit Mtb 20S over the human counterpart by as much as 74-fold. Moreover, they can penetrate the mycobacterial cell envelope and render Mtb susceptible to nitric oxide-mediated stress. Importantly, they do not inhibit the growth of human cell lines in vitro and thus may be starting points for tuberculosis drug development.