Methionyl-tRNA Synthetase inhibitors can be developed as novel Giardiasis therapeutics

甲硫氨酰-tRNA 合成酶抑制剂可开发为新型贾第鞭毛虫病疗法

• 批准号: 10598058
• 负责人: Kayode K Ojo
• 金额: $ 78.29万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-14 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10598058
• 关键词: Address; Ames Assay; Biological Assay; Biological Availability; Cell Culture Techniques; Cells; Cessation of life; Chemicals; Child; Chronic; Chronic diarrhea; Clinical; Clinical Treatment; Complementary therapies; Cyst; Data; Development; Diarrhea; Disease; Dose; Drug Kinetics; Engineering; Enzymes; Feedback; Gastrointestinal tract structure; Giardia; Giardia lamblia; Giardiasis; Goals; Growth; Health Benefit; HepG2; Human; Immunocompromised Host; In Vitro; Incidence; Infant; Infection; Intestines; Ion Channel; Lead; Libraries; Liquid substance; Luciferases; Malabsorption Syndromes; Mammalian Cell; Measures; Metabolism; Methionine-tRNA Ligase; Metronidazole; Metronidazole resistance; Micronucleus Tests; Microsomes; Mitochondria; Modeling; Molecular Mechanisms of Action; Monitor; Mutagenesis; Oral; Order Coleoptera; Parasites; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Property; Protein Biosynthesis; Proteins; Public Health; Rattus; Reporter; Research Proposals; Resistance; Resource-limited setting; Rodent Model; Safety; Series; Signal Transduction; Stomach; Structure; Symptoms; System; Techniques; Testing; Therapeutic; Time; Toxic effect; Toxicology; Trypanosoma brucei brucei; Work; alternative treatment; analog; candidate selection; chemical property; chemical synthesis; chemotherapy; chronic infection; cognitive function; cost; cytotoxicity; design; drug efficacy; effective therapy; efficacy evaluation; efficacy study; efficacy testing; enzyme activity; experimental study; functional group; gastrointestinal; imaging modality; improved; in vivo; in vivo imaging system; indexing; inhibitor; innovation; lead optimization; meetings; meter; mouse model; nanoluciferase; novel; novel therapeutics; pharmacologic; pre-clinical; prevent; receptor; residence; response; scaffold; scale up; screening; symptom treatment; tomography; treatment duration

Project Summary/Abstract Giardia lamblia is the causative agent of giardiasis, a gastrointestinal illness with symptoms including diarrhea and malabsorption. Chronic infections can lead to long term growth retardation or death in infants, with a recent estimate of global incidence of 280 million symptomatic cases per year. However, a substantial number of clinical infections are resistant to currently available treatments, especially metronidazole. We have shown that specific inhibitors of methionyl-tRNA synthetase (MetRS) representing 3 scaffolds in an available ~600 library prevent growth in wild-type and metronidazole resistant G. lamblia strains. The molecular mechanism of action seems to be the disruption of G. lamblia protein synthesis due to inhibition of GlMetRS enzyme activities. Proof of principle compound 1717 has decent oral bioavailability and is an effective treatment in a mouse model of giardiasis, showing complete clearance of G. lamblia after 3 days. This research proposal will capitalize on these encouraging preliminary data to develop compounds as novel anti-giardia drugs for alternative or complementary treatment of giardiasis. We have selected 18 compounds representing 3 distinct scaffolds based on chemical functional group diversity, GlMetRS IC50 ≤50nM, G. lamblia trophozoite EC50 ≤3000nM, and a selectivity index of ≥ 15 defined as CC50/EC50, for toxicity in HepG2 cell cultures. Preliminary data showed that the double-ring linker series tends to have better selectivity when compared to the other two series. We will therefore focus on the double-ring linker compounds. Since the pharmacokinetic correlations for effective anti-Giardia chemotherapy have not been well established, we will use these compounds to define the PK/PD properties necessary for optimum in vivo efficacy in Aim 1. Also, in Aim 1, we will determine structural activity relationships and select compounds with high potency against GlMetRS and multiple G. lamblia strains. In Aim 2, we will determine: static vs. cidal properties, rate of killing, propensity for acquired resistance and initial safety liabilities of the compounds. A combination of structure-based design, empirical SAR-driven approaches and automated quantitative tomography of G. lamblia will be used in Aim 3 to guide medicinal chemistry optimization of double- ring linker scaffold for improved efficacy and PK/ADMET properties, while addressing potential safety issues. We will determine potential toxicity and off-target effects of GlMetRS inhibitors in vitro and in rodent models. The compounds will be tested for hERG liabilities and CYP inhibition, as well as against the mutagenesis model and a safety panel of human receptors and ion channels. This will set the stage in Aim 4 for dose finding experiments in efficacy models, final toxicology studies, additional resistance studies and metronidazole combination studies. The proposed work will complete many of the steps necessary for selecting a preclinical candidate that will facilitate innovative, shorter course therapy for G. lamblia-associated chronic asymptomatic diseases, diarrhea, growth retardation, and poor cognitive function. The product will provide a great public health benefit.

项目总结/摘要 贾第虫是贾第虫病的病原体，贾第虫病是一种胃肠道疾病，症状包括腹泻 和吸收不良。慢性感染可导致婴儿长期生长迟缓或死亡， 估计全球发病率为每年2.8亿例有症状病例。然而，大量的临床 感染对目前可用的治疗，特别是甲硝唑有抗性。我们已经证明， 甲硫氨酰-tRNA合成酶（MetRS）抑制剂代表了约600个可用文库中的3种支架， 在野生型和甲硝唑抗性G.兰氏菌株。作用的分子机制似乎 是G.由于抑制GlMetRS酶活性，Lamblia蛋白质合成。证明 主要化合物1717具有良好的口服生物利用度，并且是治疗小鼠糖尿病的有效方法。 贾第虫病，显示完全清除G。3天后的兰布利亚。这项研究计划将利用这些 鼓励初步数据开发化合物作为新的抗贾第虫药物， 贾第虫病的治疗我们选择了18种化合物，代表3种不同的支架， 功能基团多样性，GlMetRS IC_（50）≤ 50 nM，G.兰氏藻滋养体EC 50 ≤ 3000 nM，选择性指数 对于HepG 2细胞培养物中的毒性，定义为CC 50/EC 50。初步数据显示， 当与其它两个系列相比时，连接体系列倾向于具有更好的选择性。因此，我们将重点关注 双环连接体化合物。由于有效的抗贾第虫药代动力学相关性 化疗尚未得到很好的建立，我们将使用这些化合物来定义PK/PD特性 目的1中的最佳体内功效所必需的。此外，在目标1中，我们将确定结构活动关系 并选择对GlMetRS和多种G.兰氏菌株。在目标2中，我们将 确定：静态与杀灭特性、杀灭率、获得性抗性倾向和初始安全责任 的化合物。基于结构的设计、经验SAR驱动的方法和自动化 G. Lamblia将用于目标3，以指导药物化学优化双- 环连接体支架用于改善功效和PK/ADMET性质，同时解决潜在的安全性问题。 我们将在体外和啮齿动物模型中确定GlMetRS抑制剂的潜在毒性和脱靶效应。的 将测试化合物的hERG责任和hERG抑制，以及针对诱变模型， 人体受体和离子通道的安全面板。这将为目标4中的剂量探索实验奠定基础 在疗效模型、最终毒理学研究、额外的耐药性研究和甲硝唑联合研究中。 拟议的工作将完成选择临床前候选人所需的许多步骤， 促进创新，更短的疗程治疗G。与兰氏相关的慢性无症状疾病，腹泻， 生长迟缓和认知功能差该产品将为公众健康带来巨大益处。