دورية أكاديمية
Orally Active and Selective Tubulin Inhibitors as Anti-Trypanosome Agents.
العنوان: | Orally Active and Selective Tubulin Inhibitors as Anti-Trypanosome Agents. |
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المؤلفون: | Vishal Nanavaty, Rati Lama, Ranjodh Sandhu, Bo Zhong, Daniel Kulman, Viharika Bobba, Anran Zhao, Bibo Li, Bin Su |
المصدر: | PLoS ONE, Vol 11, Iss 1, p e0146289 (2016) |
بيانات النشر: | Public Library of Science (PLoS), 2016. |
سنة النشر: | 2016 |
المجموعة: | LCC:Medicine LCC:Science |
مصطلحات موضوعية: | Medicine, Science |
الوصف: | OBJECTIVES:There is an urgent need to develop a safe, effective, orally active, and inexpensive therapy for African trypanosomiasis due to the drawbacks of current drugs. Selective tubulin inhibitors have the potential to be promising drug candidates for the treatment of this disease, which is based on the tubulin protein structural difference between mammalian and trypanosome cells. We propose to identify novel tubulin inhibitors from a compound library developed based on the lead compounds that selectively target trypanosomiasis. METHODS:We used Trypanosoma brucei brucei as the parasite model, and human normal kidney cells and mouse microphage cells as the host model. Growth rates of both trypanosomes and mammalian cells were determined as a means to screen compounds that selectively inhibit the proliferation of parasites. Furthermore, we examined the cell cycle profile of the parasite and compared tubulin polymerization dynamics before and after the treatment using identified compounds. Last, in vivo anti-parasite activities of these compounds were determined in T. brucei-infected mice. RESULTS:Three compounds were selected that are 100 fold more effective against the growth of T. brucei cells than mammalian cells. These compounds caused cell cycle progression defects in T. brucei cells. Western analyses indicated that these compounds decreased tubulin polymerization in T. brucei cells. The in vivo investigation revealed that these compounds, when admitted orally, inhibited T. brucei cell proliferation in mouse blood. However, they were not potent enough to clear up the infection completely. CONCLUSIONS:These compounds are promising lead compounds as orally active agents for drug development of anti-trypanosome agents. A more detail structure activity relationship (SAR) was summarized that will be used to guide future lead optimization to improve the selectivity and potency of the current compounds. |
نوع الوثيقة: | article |
وصف الملف: | electronic resource |
اللغة: | English |
تدمد: | 1932-6203 |
Relation: | http://europepmc.org/articles/PMC4714897?pdf=render; https://doaj.org/toc/1932-6203 |
DOI: | 10.1371/journal.pone.0146289 |
URL الوصول: | https://doaj.org/article/d5972f84c8d44028a728d7845a67942a |
رقم الأكسشن: | edsdoj.5972f84c8d44028a728d7845a67942a |
قاعدة البيانات: | Directory of Open Access Journals |
تدمد: | 19326203 |
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DOI: | 10.1371/journal.pone.0146289 |