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Molecular pathways affected by drugs that disrupt Na+ and lipid homeostasis in malaria parasites

破坏疟原虫中钠和脂质稳态的药物影响的分子途径

基本信息

批准号：
10659924
负责人：
AKHIL B VAIDYA
金额：
$ 71.2万
依托单位：
DREXEL UNIVERSITY
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：
2017-05-05 至 2027-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10659924
关键词：
ATP phosphohydrolase Active Biological Transport Affect Antimalarials Biochemical Biological Biology Carbon Cell Cycle Cell membrane Cells Chemicals Cholesterol Cholesterol Homeostasis Chromosome Segregation Clinical Trials Collection Complex Cytolysis Cytoplasm DNA metabolism Development Drug Targeting Drug resistance Enzymes Event Exposure to Fatty Acids Funding Genetic Goals Homeostasis Homo Knowledge Lipids Malaria Membrane Metabolic Metabolism Molecular Morphology Parasites Pathway interactions Patients Pediatric Hospitals Pharmaceutical Preparations Phase Phenotype Philadelphia Physiology Plasmodium Plasmodium falciparum Play Process Protein Dephosphorylation Protein phosphatase Proteins Research Personnel Role Signal Transduction Sodium Structure Universities Work drug discovery fatty acid transport genetic manipulation inhibitor insight interdisciplinary approach lipid transport nuclear division premature prevent recruit response rhoptry smoothened signaling pathway

项目摘要

Project Summary In recent years, several chemically diverse compounds have been identified that target PfATP4, a P-type ATPase involved in maintaining Na+ homeostasis in malaria parasites. Some of these compounds have advanced to clinical trials. Thus, PfATP4-active compounds are among the most attractive new antimalarials being developed to counter the continuing threat of drug resistance. Over the previous funding period, we have discovered some dramatic alterations in parasite physiology that accompany a short 2 h exposure to PfATP4 inhibitors. These include: i) Rapid alterations in lipid homeostasis within the parasites with reversible accumulation of cholesterol in the parasite plasma membrane (PPM); ii) Morphological changes resembling premature schizogony; and iii) Massive dephosphorylation of parasite proteins that may underlie the metabolic slowdown that follows PfATP4 inhibition. These observations reveal a collection of hitherto unknown interrelated molecular pathways, disruptions of which result in parasite demise. We found that PfATP4 inhibition appears to result in inhibition of PfNCR1, another druggable transporter, that is involved in maintaining lipid/cholesterol homeostasis within the PPM. Reduction of cholesterol content of the RBC plasma membrane results in dramatic expulsion of trophozoites from the host cell without the lysis of the RBC membrane. Remarkably, treatment with either PfATP4 or PfNCR1 inhibitors prevents this expulsion. These studies suggest an active transport of cholesterol between the RBC plasma membrane and the parasite. We found that trophozoite stage parasites exposed to PfATP4 inhibitors for just 2 h undergo massive morphological changes that resemble premature onset of schizogony events including the formation of inner membrane complexes, rhoptry-like structures and karyokinesis. In addition, trophozoites undergo massive reduction of a large number of metabolites suggestive of metabolic shutdown. We hypothesize that underlying all these events is a signaling cascade unleashed by the influx of Na+ into parasite cytoplasm following PfATP4 inhibition. In support of this proposition, we found dephosphorylation of a large number of proteins, prominent among which were molecules involved in DNA metabolism, chromosome segregation and cell cycle processes. The complexity of events triggered by PfATP4 inhibition requires a multidisciplinary approach. For this purpose, we have recruited outstanding co-investigators in consortium arrangements for the next funding period. Together, we propose to carry out the following specific aims: i) Investigate the relationship between cholesterol dynamics and its role in fatty acid and lipid transport in P. falciparum; ii) Explore the significance of dephosphorylation of proteins that follows PfATP4 inhibition; iii) Examine the causes of metabolic slowdown following PfATP4 inhibition; iv) Derive structural information for PfATP4 and PfNCR1 to understand molecular details about these validated antimalarial drug targets.

项目总结