SQ109, a New Drug Lead for Chagas Disease
文献类型：期刊论文
| 作者 | Veiga-Santos, Phercyles1,2; Li, Kai3; Lameira, Lilianne1; Ulisses de Carvalho, Tecia Maria1,2; Huang, Guozhong4,5; Galizzi, Melina4,5; Shang, Na6; Li, Qian6; Gonzalez-Pacanowska, Dolores7; Hernandez-Rodriguez, Vanessa8 |
| 刊名 | ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
 |
| 出版日期 | 2015-04-01 |
| 卷号 | 59期号:4页码:1950-1961 |
| 英文摘要 | We tested the antituberculosis drug SQ109, which is currently in advanced clinical trials for the treatment of drug-susceptible and drug-resistant tuberculosis, for its in vitro activity against the trypanosomatid parasite Trypanosoma cruzi, the causative agent of Chagas disease. SQ109 was found to be a potent inhibitor of the trypomastigote form of the parasite, with a 50% inhibitory concentration (IC50) for cell killing of 50 +/- 8 nM, but it had little effect (50% effective concentration [EC50], similar to 80 mu M) in a red blood cell hemolysis assay. It also inhibited extracellular epimastigotes (IC50, 4.6 +/- 1 mu M) and the clinically relevant intracellular amastigotes (IC50, similar to 0.5 to 1 mu M), with a selectivity index of similar to 10 to 20. SQ109 caused major ultrastructural changes in all three life cycle forms, as observed by light microscopy, scanning electron microscopy (SEM), and transmission electron microscopy (TEM). It rapidly collapsed the inner mitochondrial membrane potential (Delta psi(m)) in succinate-energized mitochondria, acting in the same manner as the uncoupler FCCP [carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone], and it caused the alkalinization of internal acidic compartments, effects that are likely to make major contributions to its mechanism of action. The compound also had activity against squalene synthase, binding to its active site; it inhibited sterol side-chain reduction and, in the amastigote assay, acted synergistically with the antifungal drug posaconazole, with a fractional inhibitory concentration index (FICI) of 0.48, but these effects are unlikely to account for the rapid effects seen on cell morphology and cell killing. SQ109 thus most likely acts, at least in part, by collapsing Delta psi/Delta pH, one of the major mechanisms demonstrated previously for its action against Mycobacterium tuberculosis. Overall, the results suggest that SQ109, which is currently in advanced clinical trials for the treatment of drug-susceptible and drug-resistant tuberculosis, may also have potential as a drug lead against Chagas disease. |
| WOS标题词 | Science & Technology ; Life Sciences & Biomedicine |
| 类目[WOS] | Microbiology ; Pharmacology & Pharmacy |
| 研究领域[WOS] | Microbiology ; Pharmacology & Pharmacy |
| 关键词[WOS] | TRYPANOSOMA SCHIZOTRYPANUM CRUZI ; SQUALENE SYNTHASE INHIBITORS ; IN-VITRO ; CHOLESTEROL-BIOSYNTHESIS ; LEISHMANIA-AMAZONENSIS ; ANTITUBERCULAR DRUG ; STEROL COMPOSITION ; AMIODARONE ; EPIMASTIGOTES ; KETOCONAZOLE |
| 收录类别 | SCI |
| 语种 | 英语 |
| WOS记录号 | WOS:000354993700017 |
| 源URL | [http://124.16.173.210/handle/834782/1484]  |
| 专题 | 天津工业生物技术研究所_结构生物学与蛋白酶学实验室 郭瑞庭_期刊论文 |
| 作者单位 | 1.Univ Fed Rio de Janeiro, Inst Biofis Carlos Chagas Filho, Lab Ultraestrutura Celular Hertha Meyer, CCS, BR-21941 Rio De Janeiro, Brazil 2.Univ Fed Rio de Janeiro, Inst Nacl Ciencia & Tecnol Biol Estrutural & Bioi, Rio De Janeiro, Brazil 3.Univ Illinois, Dept Chem, Urbana, IL 61801 USA 4.Univ Georgia, Ctr Trop & Emerging Global Dis, Athens, GA 30602 USA 5.Univ Georgia, Dept Cellular Biol, Athens, GA 30602 USA 6.Chinese Acad Sci, Tianjin Inst Ind Biotechnol, Ind Enzymes Natl Engn Lab, Tianjin, Peoples R China 7.CSIC, Inst Parasitol & Biomed Lopez Neyra, Granada, Spain 8.Inst Estudios Avanzados IDEA, Lab Senalizac Celular & Bioquim Parasitos, Caracas, Venezuela 9.Inst Venezolano Invest Cient, Caracas, Venezuela 10.Inst Nacl Metrol Qualidade & Tecnol Inmetro, Rio De Janeiro, Brazil |
| 推荐引用方式 GB/T 7714 | Veiga-Santos, Phercyles,Li, Kai,Lameira, Lilianne,et al. SQ109, a New Drug Lead for Chagas Disease[J]. ANTIMICROBIAL AGENTS AND CHEMOTHERAPY,2015,59(4):1950-1961. |
| APA | Veiga-Santos, Phercyles.,Li, Kai.,Lameira, Lilianne.,Ulisses de Carvalho, Tecia Maria.,Huang, Guozhong.,...&Oldfield, Eric.(2015).SQ109, a New Drug Lead for Chagas Disease.ANTIMICROBIAL AGENTS AND CHEMOTHERAPY,59(4),1950-1961. |
| MLA | Veiga-Santos, Phercyles,et al."SQ109, a New Drug Lead for Chagas Disease".ANTIMICROBIAL AGENTS AND CHEMOTHERAPY 59.4(2015):1950-1961. |
入库方式： OAI收割
来源：天津工业生物技术研究所
浏览0
下载0
收藏0
其他版本
除非特别说明，本系统中所有内容都受版权保护，并保留所有权利。