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Malaria melatonin receptor signaling as a novel drug target

疟疾褪黑激素受体信号传导作为新的药物靶点

基本信息

批准号：
8459979
负责人：
ANDREW P THOMAS
金额：
$ 7.09万
依托单位：
UNIV OF MED/DENT OF NJ-NJ MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-04-16 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8459979
关键词：
Affect Affinity Affinity Chromatography Anemia Antimalarials Binding Proteins Biological Assay Biology Blood Calcium Calcium Signaling Cell Culture Techniques Cell Cycle Cell Cycle Progression Cell Proliferation Cells Cerebral Malaria Chemicals Child Circadian Rhythms Clinical Cloning Combined Modality Therapy Complex Cyclic AMP Cytolysis Data Development Disease Dose Drug Industry Drug Targeting Drug effect disorder Erythrocytes Family Fever Flow Cytometry GTP-Binding Proteins Gel Goals Gold Homeostasis Hormone Receptor Hormones Hour Human Image Immune system In Vitro Infection Inositol Lead Libraries Life Life Cycle Stages Liver Malaria Melatonin Melatonin Receptors Modeling Morbidity - disease rate Nature Organ failure Parasitemia Parasites Parasitology Pathway interactions Patients Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacologic Substance Pharmacotherapy Pineal gland Plant Resins Plasmodium Plasmodium falciparum Play Production Publications Reagent Receptor Gene Receptor Signaling Resistance Resistance development Rodent Rodent Model Role Second Messenger Systems Serotonin Signal Pathway Signal Transduction Specificity Staging Symptoms Synthesis Chemistry Techniques Testing Therapeutic Time Treatment Efficacy Validation Work combat fluorescence imaging gene cloning in vivo inhibitor/antagonist interest mortality multidisciplinary novel receptor research study response second messenger small molecule tool vector mosquito

项目摘要

DESCRIPTION (provided by applicant): Malaria is a leading cause of morbidity and mortality in the Third World and resistance of Plasmodium parasites to antimalarial treatments is a significant and growing problem. Novel drug targets and treatment approaches are urgently required, but this is an under-resourced problem in the pharmaceutical industry. The purpose of this proposal is to validate a malarial signaling pathway as a novel drug target, using a subset of compounds with antimalarial activity recently released by a major pharmaceutical company, together with a related group of compounds already validated for other clinical uses. The proposed target is a malarial melatonin receptor (pMTR) that is postulated to subvert the host hormone melatonin to regulate parasite proliferation and entrain the Plasmodium cell cycle to be synchronized with the host circadian rhythm. Validation of pMTR as a potential target for small molecule drug therapy would represent a paradigm shift, both in terms of the novel pathway identified and the proposed mechanism of therapeutic action. The present work is focused on the red blood cell (RBC) stage of P. falciparum infection, which is responsible for the predominant disease symptoms, including anemia, cerebral malaria, multi-organ failure and, significantly, periodic fevers that occur on a 48 h cycle. Our previous studies have provided evidence that melatonin can initiate an intracellular calcium signaling cascade involving the second messenger IP3, leading to enhanced parasitemia and stimulating progression through the cell cycle. We hypothesize that the Plasmodia melatonin receptor (pMTR) represents a novel antimalarial drug target to decrease proliferation and synchronization of the RBC cycle. The specific aims of the proposed project are: 1. To validate pMTR as a potential small molecule chemical target and assess the effects of putative pMTR modulators on P. falciparum proliferation and synchronization. These studies will determine an initial activity profile and elucidate the mechanism of drug action, while at the same time providing additional information on the pMTR signaling pathway. 2. To develop chemical probe-derived affinity reagents to identify the pMTR protein, with the eventual goal to annotate and clone the gene. 3. To determine the efficacy of pMTR modulators in combination with established antimalarial drugs that are not thought to act through the pMTR calcium signaling pathway. 4. To examine the effect of the small molecule inhibitors of pMTR identified in Aim 1 in vivo using rodent models, in order to further assess the viability of pMTR as a potential small molecule drug target. The work will be carried out by a multidisciplinary team, with expertise in calcium and G-protein signaling, malaria biology, parasitology, chemical biology and medicinal chemistry. Techniques include live-cell fluorescence imaging, imaging flow cytometry, in vivo malaria models, and synthetic chemistry.

描述（由申请人提供）：疟疾是第三世界发病率和死亡率的主要原因，疟原虫对抗疟疾治疗的耐药性是一个重要且日益严重的问题。迫切需要新的药物靶点和治疗方法，但这是制药行业资源不足的问题。本提案的目的是验证疟疾信号通路作为一种新的药物靶点