Novel Therapeutics Targeting Giardia Kinases

摘要 肠道寄生虫贾第虫引起的感染需要新的治疗方法。目前批准的药物 具有有限的毒性，并且在高达20%的病例中由于耐药性而无效。我们发现了一组 贾第虫基因组中的蛋白激酶，在其活性部位具有不寻常的结构特征。这一特点， 一个化学上很小的看门人残基，赋予对一类称为"碰撞"激酶的化合物的敏感性。 抑制剂（BKI）不抑制哺乳动物激酶。BKI通常显示出良好的药理学特性 并且当在其他工作过程中施用时，在小鼠中显示出最小的毒性。我们有 初步研究表明，即使不完全敲除这些小的看门人激酶， 严重损害贾第虫的生长。我们还表明，BKI在培养中对贾第虫有活性。我们 将使用遗传和化学探针来严格验证这些激酶作为药物靶点。我们将确认， BKI被发现通过抑制特异性的 激酶。主要目标是使用SAR指导的合成化学来开发口服的化合物， 生物可利用的、足够有效的、无毒性的和治愈贾第虫感染的动物模型。在年底前 我们希望项目中的先导化合物能作为潜在的抗贾第鞭毛虫药物进行评价。

Abstract New therapeutics are needed for infections caused by the intestinal parasite Giardia. Current approved drugs have limiting toxicity and are ineffective dur to resistance in up to 20% of cases. We have identified a set of protein kinases in the Giardia genome that share an unusual structure feature in their active site. This feature, an atypically small gatekeeper residue, confers sensitivity to a class of compounds called "bumped" kinase inhibitors (BKI) that do not inhibit mammalian kinases. BKIs in general show good pharmacological properties and have shown minimal toxicity in mice when administered in the course of other work. We have demonstrated in preliminary work that even incomplete knockdown of these small-gatekeeper kinases significantly impairs Giardia growth. We have also shown that BKIs are active against Giardia in culture. We will use genetic and chemical probes to rigorously validate these kinases as drug targets. We will confirm that BKIs found to be active in suppressing Giardia growth, cell attachment, or encystation act by inhibiting specific kinases. 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 potential drugs against giardiasis.