Inhibitors of Plasmodium liver infection

疟原虫肝脏感染抑制剂

基本信息

批准号：
9386161
负责人：
Purnima Bhanot
金额：
$ 19.88万
依托单位：
RBHS-NEW JERSEY MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-05-25 至 2019-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9386161
关键词：
Address Adverse effects Antimalarials Antiparasitic Agents Area Binding Proteins Biological Assay Biological Availability Biology Cells Chemicals Collaborations Crystallization Cyclic GMP-Dependent Protein Kinases Data Development Digit structure Disease Disease Outbreaks Dose Drug Design Drug Kinetics Drug Targeting Drug resistance Drug usage Drug-sensitive Eimeria tenella Ensure Enzymes Erythrocytes Future Genes Goals HepG2 Hepatocyte Human Image Immunity In Vitro Individual Infection Injectable Interruption Invaded KRP protein Lead Life Cycle Stages Liver Liver Microsomes Luciferases Luminescent Measurements Malaria Measures Metabolic Modeling Mus Nature Oral Oral Administration Parasitemia Parasites Pathology Permeability Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacodynamics Phosphotransferases Plasma Proteins Plasmodium Plasmodium falciparum Plasmodium vivax Prevention Property Protein Kinase Recombinants Relapse Resistance Resources Roentgen Rays Safety Selection Criteria Specificity Sporozoites Structure Techniques Testing Time Toxic effect Toxicity Tests Work absorption analog asexual cost design disparity reduction experience improved in vitro testing in vivo in vivo imaging system inhibitor/antagonist intravenous administration kinase inhibitor liver infection novel novel therapeutics physical property preclinical development prevent programs prophylactic response tissue culture transmission process

项目摘要

ABSTRACT Malaria is caused by the protozoan parasite, Plasmodium. It begins with the infection by Plasmodium sporozoites of the liver. This step is essential for the expansion of parasite numbers and the subsequent symptomatic erythrocytic cycle. Dormant liver stages formed by P. vivax are the major cause of malaria relapses. Therefore, inhibition of pre-erythrocytic infection will prevent malaria pathology and relapses from P. vivax. Current drugs against pre-erythrocytic stages have significant side-effects or are expensive. Therefore, there is an urgent need for new drugs against pre-erythrocytic stages. We propose to initiate a medicinal chemistry effort to optimize an inhibitor of P. falciparum's cGMP-dependent protein kinase (PKG). PKG is essential for sporozoite invasion of hepatocytes and subsequent development in liver stages. Its chemical inhibition by a trisubstituted pyrolle (TSP) prevents liver infection in tissue culture assays and in mice. We hypothesize that optimization of TSP's physical properties will yield compounds with low dose efficacy against P. berghei liver stages. Our collaborative work combines expertise and experience in pre-erythrocytic stage biology and kinases, medicinal chemistry of kinase inhibitors and computational drug design. Our specific aims are: Specific Aim 1: Design and synthesize novel TSP analogs. Medicinal chemistry techniques guided by P. falciparum PKG (PfPKG) X-ray crystal structure will be used to synthesize analogs predicted to have improved potency and permeability properties. Specific Aim 2: Determine in vitro potency and liver stage activity of TSP analogs. Potency against PfPKG enzyme, whole-cell activity against P. falciparum erythrocytic stages and P. berghei sporozoite infection of HepG2 cells, ADME, toxicity and specificity studies will be considered in selecting parasite-selective compounds for testing in Aim 3 Specific Aim 3: Determine in vivo efficacy of TSP analogs. Compounds (single concentration, multiple dosing) will be tested through oral and intravenous administration to mice infected with luciferase-expressing P. berghei sporozoites. Liver stage infection will be quantified using luminescence measurements. Compounds that significantly inhibit liver parasitemia are likely to possess reasonable pharmacokinetic and pharmacodynamics properties, appropriate for future optimization.

抽象的疟疾是由原生动物寄生虫疟原虫引起的。它始于疟原虫子孢子的感染肝。此步骤对于寄生虫数量的扩大和随后的有症状的红细胞周期至关重要。间日疟原虫形成的休眠肝脏阶段是疟疾复发的主要原因。因此，抑制前红细胞感染将预防间日疟原虫引起的疟疾病理学和复发。目前针对红细胞前阶段的药物有副作用大或者价格昂贵。因此，迫切需要针对红细胞前阶段的新药物。我们建议启动一项药物化学工作，以优化恶性疟原虫 cGMP 依赖性蛋白的抑制剂激酶（PKG）。 PKG 对于子孢子侵入肝细胞以及随后肝脏阶段的发育至关重要。它是三取代吡咯 (TSP) 的化学抑制可防止组织培养测定和小鼠体内的肝脏感染。我们假设优化 TSP 的物理特性将产生对疟原虫具有低剂量功效的化合物。伯盖伊肝阶段。我们的合作工作结合了红细胞前阶段生物学的专业知识和经验，激酶、激酶抑制剂的药物化学和计算药物设计。我们的具体目标是：具体目标 1：设计和合成新型 TSP 类似物。以恶性疟原虫为指导的药物化学技术 PKG (PfPKG) X 射线晶体结构将用于合成预计具有改进效力和渗透性能。具体目标 2：确定 TSP 类似物的体外效力和肝阶段活性。对抗 PfPKG 酶的效力，针对 HepG2 细胞的恶性疟原虫红细胞阶段和伯氏疟原虫子孢子感染的全细胞活性，ADME，在选择寄生虫选择性化合物进行目标 3 测试时将考虑毒性和特异性研究具体目标 3：确定 TSP 类似物的体内功效。化合物（单一浓度、多次给药）将通过口服和静脉注射给感染表达荧光素酶的伯氏疟原虫子孢子的小鼠进行测试。将使用发光测量来量化肝阶段感染。显着抑制肝脏的化合物寄生虫血症可能具有合理的药代动力学和药效学特性，适合未来优化。