Activity of the Histone Deacetylase Inhibitor FR235222 on Toxoplasma gondii: Inhibition of Stage Conversion of the Parasite Cyst Form and Study of New Derivative Compounds
Activity of the Histone Deacetylase Inhibitor FR235222 on Toxoplasma gondii: Inhibition of Stage Conversion of the Parasite Cyst Form and Study of New Derivative Compounds
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DOI：
10.1128/aac.00462-10
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发表时间：
2010-11-01
影响因子：
4.9
通讯作者：
Pelloux, Herve
中科院分区：
文献类型：
--
作者：
Maubon, Daniele;Bougdour, Alexandre;Pelloux, Herve
缓殖子向速殖子的转化在免疫功能低下者眼部弓形虫病和疾病复发的发病机制中发挥着作用。目前可用的药物对包囊无效，不能防止潜伏弓形虫病的再激活。先前的研究表明，组蛋白去乙酰化酶抑制剂FR 235222对速殖子生长具有显著影响，并在体外诱导速殖子向缓殖子转化。目前的研究表明，FR 235222可以在体外靶向转换的包囊和缓殖子。此外，该化合物对离体T细胞有活性。弓形虫囊肿当用FR 235222处理包囊时，细胞壁裂解后分离的游离缓殖子在体外不增殖。结果表明，该化合物能通过T.囊状细胞壁荧光标记显示，该化合物损害了缓殖子的转化能力，而不损害囊壁的完整性。当用FR 235222处理这些包囊时，先前处理的包囊的体内接种未能感染小鼠。我们利用我们对FR 235222及其靶标T.弓形虫HDAC 3，合成新的FR 235222衍生物。我们发现了两种新的分子对速殖子有很强的抑制作用。它们具有更好的选择性指数，更适合未来的体内方法。这些结果将FR 235222及其衍生物确定为急性和慢性弓形虫病治疗药物范围内的新先导化合物。
Bradyzoite-to-tachyzoite conversion plays a role in the pathogenesis of recrudescence of ocular toxoplasmosis and disease in immunocompromised persons. The currently available medicines are ineffective on cysts and fail to prevent reactivation of latent toxoplasmosis. A previous study showed that the histone deacetylase inhibitor FR235222 has a dramatic effect on tachyzoite growth and induces tachyzoite-to-bradyzoite conversion in vitro. The present study shows that FR235222 can target in vitro-converted cysts and bradyzoites. Moreover, the compound is active on ex vivo T. gondii cysts. Free bradyzoites isolated after lysis of the cell wall did not proliferate in vitro when the cyst was treated with FR235222. The results imply that this compound is able to cross the T. gondii cystic cell wall. Fluorescent labeling shows that the compound impairs the capacity of the bradyzoites to convert without damaging the cyst wall integrity. In vivo inoculation of formerly treated cysts fails to infect mice when these cysts were treated with FR235222. We used our structural knowledge of FR235222 and its target, T. gondii HDAC3, to synthesize new FR235222 derivative compounds. We identified two new molecules that are highly active against tachyzoites. They harbor a better selectivity index that is more suitable for a future in vivo approach. These results identify FR235222 and its derivatives as new lead compounds in the range of therapeutics available for acute and chronic toxoplasmosis.