Drug Design Targeting ProRS in Anaerobic Parasites

 描述（由申请人提供）：普遍必需的酶脯氨酰-tRNA合成酶（ProRS）最近被鉴定为药物常山酮的分子靶标，常山酮衍生自具有抗疟疾活性的天然产物。常山酮表现出与疟原虫和人ProRS结合的保守模式，如通过相应药物：酶复合物的晶体结构所示。我们已经表明，常山酮也可以阻断培养物中贾第虫的生长和包囊形成，其EC 50约等于当前一线抗贾第虫病药物甲硝唑的EC 50。然而，从贾第鞭毛虫和毛滴虫物种的ProRS的活性位点显着不同的人类和疟原虫同源物，我们已经通过序列分析和确定贾第鞭毛虫ProRS晶体结构。这强烈表明，常山酮的适当修饰将增加其相对于人类宿主对贾第虫和毛滴虫寄生虫的效力和作用特异性。我们将评估这些化合物在抑制寄生虫生长、细胞附着或包囊形成中的活性。主要目标是使用SAR指导的合成化学来开发口服生物可利用的、足够有效的、无毒的化合物，并治愈贾第虫感染的动物模型。在这个项目结束时，我们希望有先导化合物作为治疗贾第虫病和滴虫病的新药进行评价。

 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.