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。当前批准的药物 毒性有限，在高达20%的病例中由于抗药性而无效。我们已经确定了一套 贾第鞭毛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。这一功能， 一种非典型的小把关残基，使其对一类名为“凹凸不平”的激酶的化合物具有敏感性。 不抑制哺乳动物激酶的抑制剂(BKI)。BKI总体上表现出良好的药理作用 在其他工作过程中给药时，对小鼠的毒性最小。我们有 在初步工作中证明，即使是不完整的敲除这些小守门人的激酶 显著损害贾第鞭毛虫的生长。我们还表明，BKI在培养上对贾第鞭毛虫很活跃。我们 将使用遗传和化学探针严格验证这些激酶作为药物靶点。我们会确认 BKIs被发现通过抑制特定的BKIs抑制贾第鞭毛虫的生长、细胞附着或包囊作用 激活剂。一个主要目标是使用合成孔径雷达引导的合成化学来开发口服的化合物 生物利用度高，效力足，无毒性，可治愈贾第虫感染的动物模型。到这个结束的时候 我们希望将先导化合物作为治疗贾第鞭毛虫病的潜在药物进行评估。

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.