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.

项目摘要/摘要 贾第鞭毛虫是贾第鞭毛虫病的病因，贾第鞭毛疾病是一种胃肠道疾病，症状包括腹泻 和吸收不良。慢性感染会导致婴儿的长期增长或死亡，最近 估计全球每年有2.8亿个有症状病例的全球事件。但是，大量的临床 感染对当前可用的治疗具有抵抗力，尤其是甲硝唑。我们已经表明了特定的 在可用的〜600库中代表3个支架的甲基二酮-TRNA合成酶（METRS）的抑制剂 野生型和甲硝唑的耐药lamblia菌株的生长。作用的分子机制似乎 是由于GLMETRS酶活性抑制而导致的lamblia蛋白合成的破坏。证明 原理化合物1717具有不错的口服生物利用度，是小鼠模型的有效治疗方法 贾第鞭毛病毒，在3天后显示了G. lamblia的完全清除。这项研究建议将利用这些 鼓励初步数据开发化合物，作为新型抗甘迪亚药物的替代或完整性药物 贾第鞭毛疾病的治疗。我们选择了18种基于化学的代表3种不同的脚手架的化合物 功能组多样性，GLMETRSIC50≤50nm，G。Lamblia滋养体EC50≤3000Nm和选择性指数 ≥15定义为CC50/EC50，用于HEPG2细胞培养物中的毒性。初步数据显示了双环 与其他两个系列相比，接头系列的选择性往往具有更好的选择性。因此，我们将专注于 双环接头化合物。由于有效抗giardia的药代动力学相关性 化学疗法尚未得到很好的确定，我们将使用这些化合物来定义PK/PD特性 AIM 1中最佳体内效率所必需的。此外，在AIM 1中，我们将确定结构活动关系 并选择具有高效力的GLMETR和多个G. lamblia菌株的化合物。在AIM 2中，我们将 确定：静态与圆柱特性，杀戮率，获得抵抗的承诺和初始安全责任 化合物。基于结构设计，经验SAR驱动方法和自动化的结合 G. lamblia的定量断层扫描将用于AIM 3，以指导双重的医学化学优化 环形接头脚手架，以提高效率和PK/ADMET特性，同时解决潜在的安全问题。 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靶向效果。这 化合物将针对HERG责任和CYP抑制，以及诱变模型和 人体受体和离子通道的安全板。这将使AIM 4的阶段进行剂量查找实验 在效率模型中，最终毒理学研究，其他抗性研究和甲硝唑组合研究。 拟议的工作将完成选择一个临床前候选人所需的许多步骤 促进与G. lamblia相关的慢性不对称疾病的创新，较短的课程疗法，腹泻， 生长迟钝，认知功能差。该产品将提供巨大的公共卫生益处。