O'Connell Elise M, Bennuru Sasisekhar, Steel Cathy, Dolan Michael A, Nutman Thomas B
Laboratory of Parasitic Diseases.
Bioinformatics and Computational Biosciences Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland.
J Infect Dis. 2015 Sep 1;212(5):684-93. doi: 10.1093/infdis/jiv065. Epub 2015 Feb 5.
Elimination of onchocerciasis and lymphatic filariasis is targeted for 2020. Given the coincident Loa loa infections in Central Africa and the potential for drug resistance development, the need for new microfilaricides and macrofilaricides has never been greater. With the genomes of L. loa, Onchocerca volvulus, Wuchereria bancrofti, and Brugia malayi available, new drug targets have been identified.
The effects of the tyrosine kinase inhibitors imatinib, nilotinib, and dasatinib on B. malayi adult males, adult females, L3 larvae, and microfilariae were assessed using a wide dose range (0-100 µM) in vitro.
For microfilariae, median inhibitory concentrations (IC50 values) on day 6 were 6.06 µM for imatinib, 3.72 µM for dasatinib, and 81.35 µM for nilotinib; for L3 larvae, 11.27 µM, 13.64 µM, and 70.98 µM, respectively; for adult males, 41.6 µM, 3.87 µM, and 68.22 µM, respectively; and for adult females, 42.89 µM, 9.8 µM, and >100 µM, respectively. Three-dimensional modeling suggests how these tyrosine kinase inhibitors bind and inhibit filarial protein activity.
Given the safety of imatinib in humans, plans are underway for pilot clinical trials to assess its efficacy in patients with filarial infections.
盘尾丝虫病和淋巴丝虫病的消除目标定在2020年。鉴于中非同时存在罗阿丝虫感染以及产生耐药性的可能性，对新型微丝蚴杀虫剂和成虫杀虫剂的需求从未如此迫切。随着罗阿丝虫、盘尾丝虫、班氏吴策线虫和马来布鲁线虫的基因组可用，已确定了新的药物靶点。
在体外使用宽剂量范围（0 - 100 μM）评估酪氨酸激酶抑制剂伊马替尼、尼洛替尼和达沙替尼对马来布鲁线虫成虫雄虫、成虫雌虫、L3幼虫和微丝蚴的作用。
对于微丝蚴，第6天的半数抑制浓度（IC50值）伊马替尼为6.06 μM，达沙替尼为3.72 μM，尼洛替尼为81.35 μM；对于L3幼虫，分别为11.27 μM、13.64 μM和70.98 μM；对于成虫雄虫，分别为41.6 μM、3.87 μM和68.22 μM；对于成虫雌虫，分别为42.89 μM、9.8 μM和>100 μM。三维建模表明了这些酪氨酸激酶抑制剂如何结合并抑制丝虫蛋白活性。
鉴于伊马替尼在人体中的安全性，正在计划进行试点临床试验以评估其在丝虫感染患者中的疗效。
