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Novel Therapeutics Targeting Giardia Kinases

针对贾第鞭毛虫激酶的新疗法

基本信息

批准号：
9221721
负责人：
ETHAN A MERRITT
金额：
$ 19.34万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-12-01 至 2018-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9221721
关键词：
Active Sites Address Affect Amino Acids Animal Model Binding Bioavailable Biological Assay Cell-Matrix Junction Cells Chemicals Collection Complex Crystallography Data Development Disease Drug Design Drug Kinetics Drug Targeting Engineering Equilibrium Evaluation Exhibits Food Contamination Gatekeeping Genetic Genome Geometry Giardia Giardiasis Goals Growth Human Human Cell Line Impairment In Situ In Vitro Individual Infection Intestinal parasite Knock-in Lead Libraries Metronidazole Metronidazole resistance Modeling Mus Oral Parasite resistance Parasitemia Parasites Pharmaceutical Preparations Pharmacology Phase Phenotype Phosphotransferases Positioning Attribute Property Protein Kinase Proteins Proteomics Protozoa Research Resistance Resistance development Ribose Set protein Structural Models Structure Synthesis Chemistry Testing Toxic effect Validation Variant Water Work base biophysical properties calcium-dependent protein kinase cytotoxicity design efficacy testing genetic inhibitor imaging modality in vitro activity in vivo inhibitor/antagonist kinase inhibitor knock-down nanomolar neglect new therapeutic target novel novel therapeutics pathogen pre-clinical research clinical testing resistant strain response scaffold scale up screening whole animal imaging

项目摘要

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.

抽象的需要新的疗法来治疗肠道寄生虫贾第鞭毛虫引起的感染。目前批准的药物毒性有限，并且在高达 20% 的病例中对耐药性无效。我们已经确定了一组贾第鞭毛虫基因组中的蛋白激酶在其活性位点具有不寻常的结构特征。这个功能，一种非典型的小守门残基，赋予对一类称为“碰撞”激酶的化合物的敏感性不抑制哺乳动物激酶的抑制剂（BKI）。 BKI 通常表现出良好的药理学特性在其他工作过程中给药时，对小鼠的毒性很小。我们有在初步工作中证明，即使这些小看门人激酶的敲除不完全显着损害贾第鞭毛虫的生长。我们还表明，BKI 在培养中对贾第鞭毛虫具有积极作用。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 被发现可通过抑制特定的酶活性来抑制贾第鞭毛虫的生长、细胞附着或成囊作用。激酶。主要目标是使用 SAR 引导的合成化学来开发口服化合物具有生物利用度、足够有效、无毒性并可治愈贾第鞭毛虫感染的动物模型。到此结束时在该项目中，我们希望获得先导化合物作为抗贾第鞭毛虫病的潜在药物进行评估。