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和死亡的主要原因，疟原虫对抗疟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。该提案的目的是使用以下子集验证疟疾信号通路作为新药物靶点一家大型制药公司最近发布了具有抗疟活性的化合物，以及一组已验证可用于其他临床用途的相关化合物。拟议的目标是疟疾褪黑激素受体（pMTR），其被认为可以破坏宿主激素褪黑激素来调节寄生虫增殖并使疟原虫细胞周期与宿主昼夜节律同步。 pMTR 作为小分子药物治疗潜在靶点的验证将代表着范式的转变，无论是在确定的新途径还是拟议的治疗作用机制方面。目前的工作重点是恶性疟原虫感染的红细胞 (RBC) 阶段，该阶段是造成主要疾病症状的原因，包括贫血、脑型疟疾、多器官衰竭，以及 48 岁以下患者出现的周期性发烧。 h 循环。我们之前的研究提供的证据表明，褪黑激素可以启动涉及第二信使 IP3 的细胞内钙信号级联反应，导致寄生虫血症增强并刺激细胞周期的进展。我们假设疟原虫褪黑激素受体（pMTR）代表了一种新的抗疟药物靶点，可以减少红细胞周期的增殖和同步。拟议项目的具体目标是： 1. 验证 pMTR 作为潜在的小分子化学靶标，并评估假定的 pMTR 调节剂对恶性疟原虫增殖和同步的影响。这些研究将确定初始活性概况并阐明药物作用机制，同时提供有关 pMTR 信号通路的附加信息。 2. 开发化学探针衍生的亲和试剂来鉴定pMTR蛋白，最终目标是注释和克隆该基因。 3. 确定 pMTR 调节剂与不被认为通过 pMTR 钙信号通路发挥作用的现有抗疟药物联合使用的功效。 4. 使用啮齿动物模型检查 Aim 1 中鉴定的 pMTR 小分子抑制剂在体内的作用，为了进一步评估 pMTR 作为潜在小分子药物靶点的可行性。这项工作将由一个多学科团队进行，他们在钙和 G 蛋白信号传导方面拥有专业知识，疟疾生物学、寄生虫学、化学生物学和药物化学。技术包括活细胞荧光成像、成像流式细胞术、体内疟疾模型和合成化学。