Drug Design Targeting ProRS in Anaerobic Parasites

 描述(由申请人提供)：最近，普遍的基本酶ProRS被确定为药物Halofugione的分子靶标，该药物从具有抗疟疾活性的天然产品中提取。从药物：酶复合体的晶体结构可以看出，常青藤酮与疟原虫和人ProRs的结合方式是保守的。我们已经证明，在培养中，常青藤酮也能抑制贾第鞭毛虫的生长和包囊，其EC50大约相当于目前一线抗贾第鞭毛虫药物甲硝唑的EC50。然而，正如我们通过序列分析和确定贾第虫ProRS的晶体结构所显示的那样，来自贾第虫和滴虫物种的ProRs的活性部位与人和疟原虫同源物的活性部位有很大的不同。这有力地表明，适当的修饰将提高其效力和相对于人类宿主的抗贾第虫和滴虫的特异性。我们将评估这些化合物在抑制寄生虫生长、细胞附着或包囊方面的活性。一个主要的目标是使用SAR引导的合成化学来开发口服生物可用、足够有效、无毒性的化合物，并治愈贾第虫感染的动物模型。到这个项目结束时，我们希望将先导化合物作为治疗贾第鞭毛虫病和滴虫病的新药进行评估。

 DESCRIPTION (provided by applicant): The universally essential enzyme prolyl-tRNA synthetase (ProRS) has recently been identified as a molecular target for the drug halofuginone, which is derived from natural products with anti-malarial activity. Halofuginone exhibits a conserved mode of binding to both plasmodium and human ProRS as shown by crystal structures of the respective drug:enzyme complexes. We have shown that halofuginone is also blocks growth and encystation of Giardia in culture with an EC50 approximately equal to that of the current front line anti-giardiasis drug metronidazole. Nevertheless the active site of ProRS from Giardia and from Trichomonas species differs significantly from that of the human and plasmodium homologs, as we have shown by sequence analysis and by determining a Giardia ProRS crystal structure. This strongly suggests that suitable modification of halofuginone will both increase its potency and its specificity of action against Giardia and Trichomonas parasites relative to the human host. We will evaluate such compounds for activity in suppressing parasite growth, cell attachment, or encystation. A primary goal is to use SAR-guided synthetic chemistry to develop compounds that are orally bioavailable, sufficiently potent, lack toxicity, and cure animal models of Giardia infection. By the end of this project we expect to have lead compounds for evaluation as new drugs against giardiasis and trichomoniasis.