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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：
9751740
负责人：
Purnima Bhanot
金额：
$ 69.47万
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 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9751740
关键词：
Address Alleles Animals Antimalarials Appearance Back Binding Proteins Biological Assay Biology Blood Cells Cellular Assay Chemicals Chemoprevention Chemoprotection Chemoprotective Agent Cyclic GMP-Dependent Protein Kinases Data Development Disease 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 appropriate dose asexual base cytotoxicity test design efficacy testing in vivo in vivo evaluation in vivo imaging system inhibitor/antagonist kinase inhibitor liver infection mouse model new therapeutic target novel novel therapeutics prevent scaffold screening side effect 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.

摘要

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Plasmodium falciparum cGMP-Dependent Protein Kinase - A Novel Chemotherapeutic Target.

DOI：
10.3389/fmicb.2020.610408
发表时间：
2020
期刊：
Frontiers in microbiology
影响因子：
5.2
作者：
Rotella D;Siekierka J;Bhanot P
通讯作者：
Bhanot P

Characterization of Competitive Inhibitors of Plasmodium falciparum cGMP-Dependent Protein Kinase.

DOI：
10.1002/cbic.202100704
发表时间：
2022-04-05
期刊：
Chembiochem : a European journal of chemical biology
影响因子：
0
作者：
通讯作者：

Discovery of Imidazole-Based Inhibitors of Plasmodium falciparum cGMP-Dependent Protein Kinase.

发现基于咪唑的恶性疟原虫 cGMP 依赖性蛋白激酶抑制剂。

DOI：
10.1021/acsmedchemlett.1c00540
发表时间：
2021
期刊：
ACS medicinal chemistry letters
影响因子：
4.2
作者：
Bheemanaboina,RammohanRYadav;deSouza,MarianaLaureano;Gonzalez,MarianaLozano;Mahmood,ShamsUl;Eck,Tyler;Kreiss,Tamara;Aylor,SamanthaO;Roth,Alison;Lee,Patricia;Pybus,BrandonS;Colussi,DennisJ;Childers,WayneE;Gordon,John;Sie
通讯作者：
Sie