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：
9033819
负责人：
ANDREW P THOMAS
金额：
$ 43.15万
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：
2012
资助国家：
美国
起止时间：
2012-04-16 至 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9033819
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 interest mortality multidisciplinary new therapeutic target novel receptor research study response second messenger small molecule small molecule inhibitor targeted treatment 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抗性是一个重大且日益严重的问题。迫切需要新颖的药物靶标和治疗方法，但这是制药行业资源不足的问题。该建议的目的是使用一部分一家大型制药公司最近发布的具有抗疟疾活性的化合物，以及已经为其他临床用途验证的相关化合物组。所提出的靶标是疟疾褪黑激素受体（PMTR），该靶标的假定是为了颠覆宿主激素褪黑激素以调节寄生虫增殖，并吸收与宿主昼夜节律同步的疟原虫细胞周期。验证PMTR作为小分子药物治疗的潜在靶标将代表范式转移，无论是在确定的新途径和所提出的治疗作用机制方面。目前的工作集中于恶性疟原虫感染的红细胞（RBC）阶段，该阶段负责主要疾病症状，包括贫血，脑疟疾，多器官衰竭以及显着的周期循环。我们以前的研究提供了褪黑激素可以引发涉及第二质体IP3的细胞内钙信号传导级联反应，从而导致寄生虫血症增强并刺激整个细胞周期的进展。我们假设疟原虫褪黑激素受体（PMTR）代表了一种新型的抗疟药靶标，可降低RBC循环的增殖和同步。拟议项目的具体目的是：1。验证PMTR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特征并阐明药物作用的机理，同时提供有关PMTR信号通路的其他信息。 2。开发化学探针衍生的亲和力试剂以鉴定PMTR蛋白，最终以注释和克隆基因的目标。 3。确定PMTR调节剂与已建立的抗疟药相结合的疗效，这些药物不被认为通过PMTR钙信号通路起作用。 4。检查使用啮齿动物模型在体内鉴定的PMTR的小分子抑制剂的作用，为了进一步评估PMTR作为潜在的小分子药物靶标的生存能力。这项工作将由一个多学科团队进行，具有钙和G蛋白信号的专业知识，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。