Discovery of Adenosine Receptor Allosteric Modulators for Cardiovascular Disease and Inflammation
Discovery of Adenosine Receptor Allosteric Modulators for Cardiovascular Disease and Inflammation
批准号:
10464473
负责人:
Courtney L Fisher
金额:
$3.95万
依托单位国家:
美国
项目类别:
财政年份:
2022
资助国家:
美国
项目状态:
已结题
起止时间:
2022-09-02 至 2023-06-14
关键词:
AccountingAdenosineAdenosine A3 ReceptorAffinityAgonistAminesAmino AcidsBasic ScienceBehaviorBindingBinding SitesBiochemicalBiologicalBiological AssayCardiotoxicityCardiovascular DiseasesCause of DeathCell LineCell physiologyCellsCellular StressCessation of lifeChemicalsChemotaxisChronicClinical TrialsCollaborationsCoupledDataDevelopmentDiseaseDisease modelDissociationDose-LimitingDrug DesignExhibitsExperimental DesignsFutureG-Protein-Coupled ReceptorsGTP-Binding Protein alpha Subunits, GsGTP-Binding ProteinsGoalsHL-60 CellsHL60Heart InjuriesHumanHypoxiaImmuneImpairmentInflammationInflammatoryKnowledgeLaboratoriesLeadLeftLigandsMedicineMentorsMolecular CloningMusMutagenesisMyocardial IschemiaNADPPharmacologyPositioning AttributeProductionProteinsPublishingPurinergic P1 ReceptorsRattusReceptor ActivationReceptor SignalingReportingResearchRodentRodent ModelRoleScientistSeriesSignal TransductionSignaling MoleculeSiteSpecificityStructureStructure-Activity RelationshipSuperoxidesTestingTherapeuticTimeUnited StatesUnited States National Institutes of HealthWomanWorkbasebiopharmaceutical industrychemotherapycostdrug developmentearly phase clinical trialefficacy evaluationexperienceimmune activationimprovedmenmutantneutrophilnovelnovel therapeuticspositive allosteric modulatorpre-clinicalpreventquinolineradioligandreceptorrepairedresponseside effectsmall moleculespatiotemporalspecies differencetherapeutic targettissue injury
中文摘要
项目总结
英文摘要
PROJECT SUMMARY
Cardiovascular disease is the leading cause of death in the United States for both men and women, costing
$351.2 billion dollars and accounting for over 840,000 deaths annually. The A3 adenosine receptor (A3AR) is a
Gi protein-coupled receptor that is highly expressed in several types of inflammatory cells, including neutrophils.
Increased adenosine levels following tissue injury/inflammation leads to activation of A3AR signaling, which aids
to limit inflammation and to promote repair, in part by impairing immune cell chemotaxis and activation. Agonists
of the A3AR are being investigated for a multitude of inflammatory diseases including cardiac ischemia and
chemotherapy-induced cardiotoxicity. Unfortunately, dose-limiting side effects have been reported in early
clinical trials potentially limiting their usefulness. Compounds that potentiate signaling of endogenous ligands,
termed positive allosteric modulators (PAMs), allow for spatiotemporal specificity, and reduced off-target effects.
It is anticipated that PAMs targeting the A3AR will offer a superior treatment approach. In these proposed studies,
I aim to characterize and further develop A3AR PAMs that will serve as small molecule probes and useful therapeutics for
cardiac injury and inflammatory disorders. Prior structure-activity-relationship studies (SAR) identified the 1H-
imidazo[4,5]quinoline-4-amine, LUF6000, and the 2,4-disubstituted quinoline, LUF6096, as exhibiting PAM
activity at the A3AR, where these modulators enhance orthosteric agonist efficacy upwards of 2-fold.
Unfortunately, they also have the undesirable tendency to decrease agonist potency. In addition, none of the
PAMs we have investigated thus far exhibit PAM activity versus rodent receptors, preventing us from assessing
biological activity in preclinical rodent models of disease. In Aim 1, I will expand on prior SAR studies by
characterizing two new series of derivatives, based off the structures of LUF6000 and LUF6096 with the goal of
identifying improved A3AR PAMs that dually enhance orthosteric agonist efficacy and potency. As part of this
aim, I will investigate whether our PAM ligands support biased (G protein-dependent vs G protein-independent)
signaling and assess for activity versus the mouse A3AR. In Aim 2, I will exploit species differences and generate
human/mouse chimeric and mutant A3ARs to facilitate identification of the binding pocket for LUF6000 and
LUF6096. Lastly, in Aim 3 I will investigate the biological effects of LUF6000 and LUF6096 on two critical
neutrophil functions - superoxide production and chemotaxis - utilizing a human neutrophilic cell line (HL60 cells).
Upon completion of these proposed studies, under the guidance of my mentor, a diverse team of collaborators,
and my dissertation committee, I will gain experience in experimental design, execution of biochemical assays,
molecular cloning, and basics of rational drug design, which will result in publishable data and prepare me to
successfully compete for a position as a research scientist at a biopharmaceutical company. Completion of this
work will advance our understanding of A3AR allosteric pharmacology and potentially lead to the development
of a new therapeutic for the treatment of ischemic heart disease and other inflammatory diseases.
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国内基金
海外基金
基于ADK/Adenosine调控DNA甲基化探讨“利湿化瘀通络”法对2型糖尿病肾病足细胞裂孔膜损伤的干预机制研究
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批准号:82074359
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项目类别:面上项目
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资助金额:55.0万元
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批准年份:2020
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负责人:安晓飞
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依托单位:
细胞外腺苷(Adenosine)作为干细胞旁分泌因子的生物学鉴定和功能分析
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批准号:81570244
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项目类别:面上项目
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资助金额:57.0万元
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批准年份:2015
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负责人:丁兆平
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依托单位:
Adenosine诱导A1/A2AR稳态失衡启动慢性低灌注白质炎性损伤及其机制
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批准号:81171113
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项目类别:面上项目
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资助金额:55.0万元
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批准年份:2011
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负责人:黄文
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依托单位: