Drug Design Targeting ProRS in Anaerobic Parasites

针对厌氧寄生虫中 ProRS 的药物设计

• 批准号: 9091419
• 负责人: ETHAN A MERRITT
• 金额: $ 25.53万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-06-17 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9091419
• 关键词: Active Sites; Adverse effects; Amino Acyl-tRNA Synthetases; Animal Model; Antimalarials; Binding; Bioavailable; Cell-Matrix Junction; Disease; Drug Design; Enzymes; Evaluation; Exhibits; Food Contamination; Giardia; Giardiasis; Goals; Growth; Halofuginone; Health; Homologous Gene; Human; Infection; Lead; Metronidazole; Modification; Multienzyme Complexes; Natural Products; Parasites; Pharmaceutical Preparations; Plasmodium; Protozoa; Sequence Analysis; Sexually Transmitted Diseases; Specificity; Structure; Synthesis Chemistry; Toxic effect; Trichomonas; Trichomonas Infections; Water; design; improved; molecular drug target; novel therapeutics; proline-tRNA

 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.