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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.

摘要疟疾是由原生寄生虫疟原虫引起的。它开始于疟原虫子孢子的感染，肝脏这一步骤对于寄生虫数量的扩大和随后的症状性红细胞周期是必不可少的。间日疟原虫形成的背肝期是疟疾复发的主要原因。因此，抑制红细胞前感染将防止疟疾病理和间日疟原虫复发。目前针对红细胞前期阶段的药物具有副作用大或价格昂贵。因此，迫切需要针对红细胞前期阶段的新药。我们建议启动药物化学努力，以优化恶性疟原虫cGMP依赖蛋白的抑制剂激酶（PKG）。PKG对于子孢子侵入肝细胞和随后在肝阶段的发育是必需的。其三取代吡咯（TSP）的化学抑制在组织培养试验和小鼠中防止肝脏感染。我们假设TSP物理性质优化将产生对P具有低剂量功效的化合物。 Berghei肝分期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。恶性疟原虫指导的药物化学技术 PKG（PfPKG）X射线晶体结构将用于合成预测具有改善的效力的类似物，渗透性能具体目的2：测定TSP类似物的体外效力和肝脏阶段活性。对PfPKG酶的效价， HepG2细胞抗恶性疟原虫红细胞期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试验时，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（单次浓度，多次给药）将在通过口服和静脉内给药感染了表达磷酸酶的伯氏疟原虫子孢子的小鼠进行测试。将使用发光测量对肝脏期感染进行定量。显著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，适用于未来优化.