Drug discovery against lyssaviruses by high thoughput screening
Drug discovery against lyssaviruses by high thoughput screening
批准号:
9218526
负责人:
Richard K. Plemper
金额:
$39.84万
依托单位国家:
美国
项目类别:
财政年份:
2016
资助国家:
美国
项目状态:
已结题
起止时间:
2016-11-15 至 2019-10-31
关键词:
AddressAggressive behaviorAnimal DiseasesAntibodiesAntiviral AgentsAutomationBehavioralBiological AssayBiologyBlood - brain barrier anatomyBrainCell LineCellsCessation of lifeChemicalsChiropteraClassificationClinicalCold ChainsComaCommunicable DiseasesComplementComputer SimulationDNA VirusesDataDevelopmentDiseaseDoseEligibility DeterminationFailureFamilyFamily memberFoundationsFutureG-substrateGTP-Binding ProteinsGoalsHumanHuman Cell LineHyperactive behaviorImmunoglobulinsImprove AccessInfectionInfluenza A virusJointsLaboratoriesLeadLibrariesLifeLyssavirusModelingMokola virusMolecular TargetMolecular VirologyMusMuscle WeaknessOpen Reading FramesOrthomyxoviridaeParalysedPenetrationPermeabilityPilot ProjectsPreclinical Drug EvaluationProphylactic treatmentProtocols documentationQuantitative Structure-Activity RelationshipRNA VirusesRNA-Directed RNA PolymeraseRabiesRabies VaccinesRabies virusReading FramesRecombinantsRegimenReporterResistanceRespiratory syncytial virusRhabdoviridaeSavingsStructure-Activity RelationshipSymptomsTestingTherapeuticTherapeutic InterventionToxic effectTreatment CostTreatment EfficacyVaccinationVaccinesValidationViralVirusVirus InhibitorsVirus Replicationassay developmentbasebioactive natural productsclinically relevantclinically significantcost effectivecounterscreencytotoxicitydesigndrug candidatedrug developmentdrug discoveryestablished cell linefunctional gainhigh throughput screeninghuman diseaseimmunoprophylaxisimprovedinhibitor/antagonistinnovationinsightmemberminiaturizenanoluciferasenervous system disordernext generationnovelnovel therapeuticspathogenpreventresponsereverse geneticsrisk minimizationscaffoldscreeningsmall moleculesmall molecule inhibitorvirus pathogenesis
中文摘要
摘要
狂犬病病毒(RABV)和狂犬病病毒属的相关病原体引起致命的神经系统疾病
每年至少有五万五千人因此死亡目前的狂犬病疫苗安全有效,
仅保护免受I型狂犬病病毒感染,但对II型狂犬病病毒无效
也会导致狂犬病的病原体这种功效差距同样延伸到人狂犬病免疫球蛋白,
其与疫苗接种结合使用,用于暴露后预防狂犬病。独立于
由于狂犬病的致病因子是一种多组型,因此目前没有可靠的治疗方案可用于狂犬病后,
出现临床症状。开发一个新药发现平台,用于识别下一代-
产生对所有临床相关狂犬病病毒属病毒组具有活性的抗狂犬病病毒候选药物,
因此迫切需要。
我们假设具有广谱抗狂犬病病毒的货架稳定且具有成本效益的小分子抑制剂
适应症谱将改善全球获得拯救生命的抗狂犬病暴露后预防,
针对新出现的狂犬病病毒不同类群的病原体,为探索
创新的狂犬病治疗方案。基于我们高度互补的多年
在药物发现检测开发、自动化药物筛选、狂犬病毒生物学和RABV方面的专业知识
因此,我们组建了一个跨学科团队,以最终解决这一未满足的临床需求。在试点
研究中,我们已经产生了一流的RABV报告菌株窝藏纳米荧光素酶的G
蛋白编码开放阅读框(RABV-ΔG-nanoLuc),诱导单周期感染,
维持在标准的生物安全条件下,开发了一种新的抗RABV药物筛选方案,
用于自动化,并将测定小型化至384孔规模。与此同时,我们建立了直接和
用于命中候选物确认和狂犬病病毒指示谱评估的正交反筛选,以及
已经开发了一个全面的面板的检测早期阶段的机械特性。在此基础上
有形的基础,我们将在这个为期3年的治疗前发现项目中充分验证高通量
筛选(HTS)方案,并使用HTS设施将测定应用于药物发现活动
在我们的实验室建立(具体目标1)。新出现的热门候选人将在反屏幕上进行验证,
在已建立的细胞系和人及小鼠原代细胞上测定的毒性和适应症谱
来源,并评估合成优化的潜力(具体目标2)。列出一个子集,
结构和机制上不同的先导候选物,保证充分的合成开发,确认命中
将进行机械表征,确定病毒逃逸特征,以及脑渗透的可能性
具体目标(3)。
英文摘要
Abstract
Rabies virus (RABV) and related pathogens of the lyssavirus genus cause a fatal neurological disease
that leads to at least 55,000 deaths annually. Whereas the current rabies vaccine is save and efficacious, it
protects only against infection by phylogroup I lyssaviruses but is ineffective against emerging phylogroup II
pathogens that also cause rabies. This efficacy gap equally extends to the human rabies immunoglobulin,
which is used in conjunction with vaccination for post-exposure prophylaxis against rabies. Independent of the
phylogroup type of the causing agent, no reliable treatment option is currently available for rabies after the
onset of clinical symptoms. The development of a novel drug discovery platform for the identification of next-
generation anti-lyssavirus drug candidates with activity against all clinically relevant lyssavirus phylogroups is
therefore urgently needed.
We hypothesize that shelf-stable and cost-effective small molecule inhibitors with broad anti-lyssavirus
indication spectrum will improve global access to life-saving anti-rabies post-exposure prophylaxis, prepare
against emerging lyssavirus pathogens of different phylogroups, and establish a foundation to explore
innovative treatment options for symptomatic rabies. Building on our highly complementary multiple-year
expertise in drug discovery assay development, automated drug screening, lyssavirus biology, and RABV
pathogenesis, we have formed an interdisciplinary team to ultimately address this unmet clinical need. In pilot
studies, we have generated a first-in-class RABV reporter strain harboring nano-luciferase in place of the G
protein encoding open reading frame (RABV-ΔG-nanoLuc) that induces a single-cycle infection and can be
maintained under standard biosafety conditions, developed a novel anti-RABV drug screening protocol suitable
for automation, and miniaturized the assay to 384-well scale. In parallel, we have established direct and
orthogonal counterscreens for hit candidate confirmation and lyssavirus indication spectrum assessment, and
have developed a comprehensive panel of assays for early-stage mechanistic characterization. Building on this
tangible foundation, we will in this 3-year pre-therapeutic discovery project fully validate the high-throughput
screening (HTS) protocol and apply the assay to a drug discovery campaign using the HTS facilities
established in our laboratory (specific aim 1). Emerging hit candidates will be verified in counterscreens,
toxicity and indication spectrum determined on established cell lines and primary cells of human and murine
origin, and the potential for synthetic optimization assessed (specific aim 2). To short-list a subset of
structurally and mechanistically distinct lead candidates that warrant full synthetic development, confirmed hits
will be mechanistically characterized, viral escape profiles determined, and the potential for brain penetration
evaluated (specific aim 3).
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Project 1 – Development of Orally Bioavailable beta-CoV Inhibitors
-
批准号:10513942
-
项目类别:
-
资助金额:$413.93万
-
财政年份:2022
-
负责人:Richard K. Plemper
-
依托单位:
Polymerase Inhibitors of Respiratory Syncytial Virus
-
批准号:10666509
-
项目类别:
-
资助金额:$68.94万
-
财政年份:2020
-
负责人:Richard K. Plemper
-
依托单位:
Polymerase Inhibitors of Respiratory Syncytial Virus
-
批准号:10425285
-
项目类别:
-
资助金额:$68.94万
-
财政年份:2020
-
负责人:Richard K. Plemper
-
依托单位:
Polymerase Inhibitors of Respiratory Syncytial Virus
-
批准号:10034283
-
项目类别:
-
资助金额:$80.7万
-
财政年份:2020
-
负责人:Richard K. Plemper
-
依托单位:
Polymerase Inhibitors of Respiratory Syncytial Virus
-
批准号:10199980
-
项目类别:
-
资助金额:$78.08万
-
财政年份:2020
-
负责人:Richard K. Plemper
-
依托单位:
Development of a Broad-Spectrum Inhibitor against Seasonal and Highly-Pathogenic Influenza Viruses
-
批准号:10544324
-
项目类别:
-
资助金额:$91.32万
-
财政年份:2019
-
负责人:Richard K. Plemper
-
依托单位:
Development of a Broad-Spectrum Inhibitor against Seasonal and Highly-Pathogenic Influenza Viruses
-
批准号:10080034
-
项目类别:
-
资助金额:$97.96万
-
财政年份:2019
-
负责人:Richard K. Plemper
-
依托单位:
Identification and Hit-to-Lead Development of Influenza A Virus Inhibitors
-
批准号:8955538
-
项目类别:
-
资助金额:$23.69万
-
财政年份:2015
-
负责人:Richard K. Plemper
-
依托单位:
Novel Therapeutics against Respiratory Syncytial Virus Infection
-
批准号:8662435
-
项目类别:
-
资助金额:$62.29万
-
财政年份:2014
-
负责人:Richard K. Plemper
-
依托单位:
Host-Directed Inhibitors of Myxovirus Replication
-
批准号:8566072
-
项目类别:
-
资助金额:$17.12万
-
财政年份:2012
-
负责人:Richard K. Plemper
-
依托单位:
Cryo-Electron and Biochemical Anaysis of Native Paramyxovirus Fusion Complexes
-
批准号:8700311
-
项目类别:
-
资助金额:$33.96万
-
财政年份:2011
-
负责人:Richard K. Plemper
-
依托单位:
Cryo-Electron and Biochemical Anaysis of Native Paramyxovirus Fusion Complexes
-
批准号:8876533
-
项目类别:
-
资助金额:$33.96万
-
财政年份:2011
-
负责人:Richard K. Plemper
-
依托单位:
Cryo-Electron and Biochemical Analysis of Native Paramyxovirus Fusion Complexes
-
批准号:8041821
-
项目类别:
-
资助金额:$35.31万
-
财政年份:2011
-
负责人:Richard K. Plemper
-
依托单位:
Cryo-Electron and Biochemical Anaysis of Native Paramyxovirus Fusion Complexes
-
批准号:8488398
-
项目类别:
-
资助金额:$33.05万
-
财政年份:2011
-
负责人:Richard K. Plemper
-
依托单位:
Cryo-Electron and Biochemical Analysis of Native Paramyxovirus Fusion Complexes
-
批准号:8291987
-
项目类别:
-
资助金额:$24.04万
-
财政年份:2011
-
负责人:Richard K. Plemper
-
依托单位:
Cryo-Electron and Biochemical Anaysis of Native Paramyxovirus Fusion Complexes
-
批准号:8595851
-
项目类别:
-
资助金额:$14.5万
-
财政年份:2011
-
负责人:Richard K. Plemper
-
依托单位:
Cryo-Electron and Biochemical Analysis of Native Paramyxovirus Fusion Complexes
-
批准号:8090559
-
项目类别:
-
资助金额:$37.99万
-
财政年份:2010
-
负责人:Richard K. Plemper
-
依托单位:
Counteracting Resistance through Host-Directed Myxovirus Inhibitors
-
批准号:7774286
-
项目类别:
-
资助金额:$23.25万
-
财政年份:2010
-
负责人:Richard K. Plemper
-
依托单位:
Counteracting Resistance through Host-Directed Myxovirus Inhibitors
-
批准号:8067978
-
项目类别:
-
资助金额:$19.18万
-
财政年份:2010
-
负责人:Richard K. Plemper
-
依托单位:
High Throughput Screening-Based Identification of Measles Virus Probes
-
批准号:7293434
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项目类别:
-
资助金额:$2.5万
-
财政年份:2007
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负责人:Richard K. Plemper
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依托单位:
海外基金