英國《自然》雜志網(wǎng)絡(luò)版9月16日發(fā)表美國一研究小組的報告說，該小組發(fā)現(xiàn)了兩種可以破壞結(jié)核桿菌防御系統(tǒng)中蛋白酶體的化合物,，這一成果有望用于開發(fā)更有效的結(jié)核病療法,。
康奈爾大學(xué)教授卡爾·內(nèi)森領(lǐng)導(dǎo)的研究小組對2萬多種物質(zhì)進(jìn)行了研究，最終發(fā)現(xiàn)有兩種化合物可以破壞結(jié)核桿菌的蛋白酶體,。對猴子及人體細(xì)胞進(jìn)行的研究顯示,，這兩種化合物只破壞蛋白酶體，而對作為宿主的猴子細(xì)胞和人體細(xì)胞不會造成任何損傷,。
內(nèi)森表示,，目前只進(jìn)行了基礎(chǔ)性研究，這兩種化合物還未通過動物或人體試驗加以確認(rèn),。盡管他們尚未開發(fā)出相應(yīng)藥品,，但這一研究表明,，研制破壞結(jié)核桿菌防御系統(tǒng)的藥物是可行的,。
蛋白酶體對結(jié)核桿菌具有重要意義,。結(jié)核桿菌進(jìn)入人體血液中后，不會像一般細(xì)菌那樣被人體免疫細(xì)胞吞噬,，而只在人體免疫系統(tǒng)抑制下處于“休眠”狀態(tài),。人體免疫系統(tǒng)會分泌化合物，破壞結(jié)核桿菌的蛋白質(zhì)以使其斃命,。然而蛋白酶體可幫助結(jié)核桿菌清理受損蛋白質(zhì),，保持其活性。因此,，尋找能使蛋白酶體喪失功能的藥物可望開辟治療結(jié)核病的新途徑,。(生物谷Bioon.com)
生物谷推薦原始出處：
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.
