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质质子引起的。它始于由疟原虫的感染肝。此步骤对于寄生虫数量的扩展和随后的症状性红细胞周期至关重要。疟原虫形成的休眠肝阶段是疟疾复发的主要原因。因此，抑制肉芽囊细胞的感染将预防疟疾病理，并从疟原虫复发。目前针对次细胞前阶段的药物具有重大副作用或昂贵。因此，迫切需要针对芽孢杆菌阶段的新药。我们建议发起药物化学努力，以优化恶性疟原虫的CGMP依赖性蛋白的抑制剂激酶（PKG）。 PKG对于肝细胞的孢子虫入侵和随后在肝脏阶段发育至关重要。它是通过三取代的Pyrolle（TSP）抑制化学抑制，可防止组织培养分析和小鼠中的肝感染。我们假设优化TSP物理特性将产生对P的剂量效率低的化合物。 Berghei肝脏阶段。我们的协作工作结合了次生型阶段生物学方面的专业知识和经验激酶，激酶抑制剂和计算药物设计的药物化学。我们的具体目的是：特定目标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的类似物，预测具有提高的效力和渗透率。特定目标2：确定TSP类似物的体外效力和肝脏阶段活性。抗Pfpkg酶的效力，针对恶性疟原虫红细胞阶段的全细胞活性和HEPG2细胞的伯格氏孢子虫感染，ADME，在选择AIM 3的寄生虫选择化合物时，将考虑毒性和特异性研究特定目标3：确定TSP类似物的体内功效。化合物（单个浓度，多种剂量）将是通过口服和静脉内给药对感染了表达荧光素酶的伯格氏杆菌的小鼠。肝脏阶段感染将通过发光测量进行定量。显着抑制肝脏的化合物寄生虫病可能具有合理的药代动力学和药效学特性，适合将来优化。