Development of inhibitors of P. falciparum cGMP dependent protein kinase (PfPKG) for malaria chemoprevention

开发用于疟疾化学预防的恶性疟原虫 cGMP 依赖性蛋白激酶 (PfPKG) 抑制剂

基本信息

批准号：
9386266
负责人：
Purnima Bhanot
金额：
$ 72.12万
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：
2017-08-01 至 2020-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9386266
关键词：
Address Adverse effects Alleles Animals Antimalarials Appearance Back Binding Proteins Biological Assay Biology Blood Cells Chemicals Chemoprevention Chemoprotection Chemoprotective Agent Cyclic GMP-Dependent Protein Kinases Data Development Disease Dose Drug Targeting Ensure Enzymatic Biochemistry Enzymes Erythrocytes Evaluation Future Genes Genetic Goals Growth HepG2 Hepatocyte Homologous Gene Human Imidazole Immune response In Vitro Incidence Infection Infection prevention Invaded Isoxazoles Lead Liver Luciferases Malaria Measures Metabolic Modeling Monitor Mus Oral Organic Chemistry Parasitemia Parasites Pathology Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacologic Substance Phosphotransferases Plasma Proteins Plasmodium Plasmodium falciparum Plasmodium vivax Prevention Price Property Pyrroles Recombinants Relapse Resistance Rodent Model Series Severities Specificity Sporozoites Structure Structure-Activity Relationship Techniques Testing Time Toxic effect Transgenic Organisms analog asexual base cytotoxicity test design efficacy testing in vivo in vivo imaging system inhibitor/antagonist kinase inhibitor liver infection mouse model new therapeutic target novel novel therapeutics prevent scaffold screening tissue/cell culture water solubility

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. 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 of Plasmodium. Our scientific premise is that inhibition of P. falciparum cGMP-dependent protein kinase (PfPKG) will block the pre-erythrocytic cycle, and impede the erythrocytic cycle. Our hypothesis is based on data demonstrating that (i) chemical inhibition of PfPKG prevents infection by P. falciparum sporozoites of tissue culture cells, and by P. berghei sporozoites of mice. (ii) Chemical or genetic inhibition of P. berghei PKG blocks development of invaded sporozoites into mature, infectious liver stages. We propose to initiate a medicinal chemistry effort to synthesize and test a new chemical series of PfPKG inhibitors. Validated hits from this series demonstrate in vitro selectivity for PfPKG, over its human homolog, in enzymatic activity assays and are activite against the parasite. We propose a medicinal chemistry effort to optimize molecules from this series to yield potent and PfPKG-selective compounds with whole-cell activity, acceptable pharmaceutical properties for in vivo testing in mice.

抽象的疟疾是由原生动物寄生虫疟原虫引起的。它始于疟原虫感染肝脏的子孢子。此步骤对于寄生虫数量的扩大以及随后的有症状的红细胞周期。抑制前红细胞感染将预防疟疾病理学和间日疟原虫复发。目前针对红细胞前阶段的药物具有显着的副作用或昂贵的。因此，迫切需要针对疟原虫红细胞前阶段的新药。我们的科学前提是，抑制恶性疟原虫 cGMP 依赖性蛋白激酶 (PfPKG) 将阻断前红细胞周期，并阻碍红细胞周期。我们的假设基于数据证明 (i) PfPKG 的化学抑制可防止组织培养细胞的恶性疟原虫子孢子和恶性疟原虫子孢子的感染。小鼠伯盖氏子孢子。 (ii) 伯氏疟原虫 PKG 的化学或遗传抑制可阻止子孢子侵入成熟的、具有传染性的肝脏阶段。我们建议启动药物化学工作来合成和测试 PfPKG 的新化学品系列抑制剂。该系列的验证结果表明，PfPKG 相对于其人类同源物的体外选择性酶活性测定并具有抗寄生虫活性。我们建议开展药物化学工作优化该系列的分子，产生具有全细胞活性的有效且 PfPKG 选择性化合物，小鼠体内测试可接受的药物特性。