英国《自然》杂志网络版9月16日发表美国一研究小组的报告说,该小组发现了两种可以破坏结核杆菌防御系统中蛋白酶体的化合物,这一成果有望用于开发更有效的结核病疗法。
康奈尔大学教授卡尔·内森领导的研究小组对2万多种物质进行了研究,最终发现有两种化合物可以破坏结核杆菌的蛋白酶体。对猴子及人体细胞进行的研究显示,这两种化合物只破坏蛋白酶体,而对作为宿主的猴子细胞和人体细胞不会造成任何损伤。
内森表示,目前只进行了基础性研究,这两种化合物还未通过动物或人体试验加以确认。尽管他们尚未开发出相应药品,但这一研究表明,研制破坏结核杆菌防御系统的药物是可行的。
蛋白酶体对结核杆菌具有重要意义。结核杆菌进入人体血液中后,不会像一般细菌那样被人体免疫细胞吞噬,而只在人体免疫系统抑制下处于“休眠”状态。人体免疫系统会分泌化合物,破坏结核杆菌的蛋白质以使其毙命。然而蛋白酶体可帮助结核杆菌清理受损蛋白质,保持其活性。因此,寻找能使蛋白酶体丧失功能的药物可望开辟治疗结核病的新途径。(生物谷Bioon.com)
生物谷推荐原始出处:
Nature 16 September 2009 | doi:10.1038/nature08357
Inhibitors selective for mycobacterial versus human proteasomes
Gang Lin1,6, Dongyang Li3,6, Luiz Pedro Sorio de Carvalho1, Haiteng Deng4, Hui Tao2, Guillaume Vogt1, Kangyun Wu1, Jean Schneider1, Tamutenda Chidawanyika1, J. David Warren2, Huilin Li3,5 & Carl Nathan1
1 Department of Microbiology and Immunology, Weill Cornell Medical College,
2 Milstein Chemistry Core Facility and Department of Biochemistry and Structural Biology, Weill Cornell Medical College, New York, New York 10065, USA
3 Biology Department, Brookhaven National Laboratory, Upton, New York 11973-5000, USA
4 Proteomics Resource Center, The Rockefeller University, New York, New York 10065, USA
5 Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, New York 11794, USA
6 These authors contributed equally to this work.
Many anti-infectives inhibit the synthesis of bacterial proteins, but none selectively inhibits their degradation. Most anti-infectives kill replicating pathogens, but few preferentially kill pathogens that have been forced into a non-replicating state by conditions in the host. To explore these alternative approaches we sought selective inhibitors of the proteasome of Mycobacterium tuberculosis. Given that the proteasome structure is extensively conserved, it is not surprising that inhibitors of all chemical classes tested have blocked both eukaryotic and prokaryotic proteasomes, and no inhibitor has proved substantially more potent on proteasomes of pathogens than of their hosts. Here we show that certain oxathiazol-2-one compounds kill non-replicating M. tuberculosis and act as selective suicide-substrate inhibitors of the M. tuberculosis proteasome by cyclocarbonylating its active site threonine. Major conformational changes protect the inhibitor-enzyme intermediate from hydrolysis, allowing formation of an oxazolidin-2-one and preventing regeneration of active protease. Residues outside the active site whose hydrogen bonds stabilize the critical loop before and after it moves are extensively non-conserved. This may account for the ability of oxathiazol-2-one compounds to inhibit the mycobacterial proteasome potently and irreversibly while largely sparing the human homologue.