CNRS UMR5525 TIMC-IMAG, Team BNI, Grenoble Alpes, CNRS, Grenoble INP, 38000 Grenoble, France.
INSERM U1209, CNRS UMR 5309, Institute for Advanced Biosciences, Team ApicoLipid, Université Grenoble Alpes, 38000 Grenoble, France.
Int J Mol Sci. 2022 Mar 17;23(6):3254. doi: 10.3390/ijms23063254.
Toxoplasmosis is a highly prevalent human disease, and virulent strains of this parasite emerge from wild biotopes. Here, we report on the potential of a histone deacetylase (HDAC) inhibitor we previously synthesized, named JF363, to act in vitro against a large panel of strains, as well as against the liver and blood stages of parasites, the causative agents of malaria. In vivo administration of the drug significantly increases the survival of mice during the acute phase of infection by , thus delaying its spreading. We further provide evidence of the compound's efficiency in controlling the formation of cysts in the brain of -infected mice. A convincing docking of the JF363 compound in the active site of the five annotated ME49 HDACs was performed by extensive sequence-structure comparison modeling. The resulting complexes show a similar mode of binding in the five paralogous structures and a quite similar prediction of affinities in the micromolar range. Altogether, these results pave the way for further development of this compound to treat acute and chronic toxoplasmosis. It also shows promise for the future development of anti- therapeutic interventions.
弓形虫病是一种高度流行的人类疾病，这种寄生虫的毒力株从野生生物区系中出现。在这里，我们报告了我们之前合成的一种组蛋白去乙酰化酶 (HDAC) 抑制剂 JF363 的潜力，该抑制剂可在体外针对大量 株以及疟原虫的肝和血液阶段发挥作用，疟原虫是疟疾的病原体。该药物的体内给药在 感染的急性阶段显著增加了小鼠的存活率，从而延迟了其传播。我们进一步提供了该化合物在控制感染小鼠脑中包囊形成方面的效率的证据。通过广泛的序列-结构比较建模，对 JF363 化合物在五个注释的 ME49 中的活性位点进行了令人信服的对接。所得复合物在五个同源结构中表现出相似的结合模式，并且在微摩尔范围内对亲和力进行了非常相似的预测。总的来说，这些结果为进一步开发该化合物以治疗急性和慢性弓形虫病铺平了道路。它也为未来开发抗疟治疗干预措施提供了希望。
