Discovery of next-generation dengue NS4B inhibitors
Discovery of next-generation dengue NS4B inhibitors
批准号:
10514156
负责人:
Christopher Sarko
金额:
$238.48万
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:
未结题
起止时间:
2022-05-16 至 2025-04-30
关键词:
ADME StudyAntiviral AgentsAntiviral TherapyAutophagocytosisBindingBiochemicalBloodBlood CellsCanis familiarisCardiovascular systemCellsClinical ManagementClinical TrialsCombined Modality TherapyComplexCountryCulicidaeDeforestationDengueDengue VirusDevelopmentDiseaseDoseDrug InteractionsDrug KineticsEnsureFundingGenerationsGoalsHepatotoxicityHumanIncidenceInfectionIntegral Membrane ProteinInterferonsInternationalJointsKnowledgeLeadMembrane ProteinsMethodsMusNeuraxisOralPathway interactionsPatientsPharmaceutical ChemistryPharmaceutical PreparationsPhasePhase I Clinical TrialsPhase II Clinical TrialsPhototoxicityPlasmaPlayPropertyProteinsProteomicsRattusRecoveryReportingResearchResistanceResistance profileRiskRodentSafetySerotypingSignal TransductionSupportive careTherapeuticToxicologyTranslational ResearchTravelValidationViralVirusVirus DiseasesVirus Replicationattributable mortalitybasecarbonate dehydrataseclimate changeclinical candidateclinical developmentclinical translationdrug candidatedrug discoverydruggable targetexperiencefitnessgenotoxicityimprovedinhibitorinhibitor therapymosquito-bornenext generationnovelpandemic preparednesspre-clinicalpreclinical developmentresistance mechanismrespiratorysafety studytoolvirology
中文摘要
项目5 -摘要
该项目的目标是发现下一代登革热NS 4 B抑制剂。我们目前有一个泛登革热
血清型NS 4 B抑制剂NITD-688在I期临床试验中。临床前结果表明,
可能会威胁到这个化合物的进一步发展因此,我们将开发第二代化合物,
减轻责任。我们将通过追求三个目标来实现这一目标。(i)优化下一代登革热
NS 4 B抑制剂。我们已经开发了一种全面的药物化学优化策略,以提高
复合特性(ii)进行临床前表征并交付IND就绪的下一代NS 4 B
抑制剂. (iii)确定NITD-688的作用方式和电阻电位。NS 4 B是一种跨膜
通过与其它病毒和宿主蛋白质相互作用而参与复制复合体的蛋白质。我们将采取
化学蛋白质组学、生物化学和细胞方法来确定化合物抑制的机制。等
这些知识可以应用于其他膜蛋白以发现抗病毒药物。
英文摘要
PROJECT 5 – ABSTRACT
The goal of this project is to discover next-generation dengue NS4B inhibitors. We currently have a pan-dengue
serotype NS4B inhibitor NITD-688 in phase I clinical trial. Preclinical results suggest two potential liabilities that
might threaten this compound for further development. Thus, we will develop a second-generation compound to
mitigate the liabilities. We will achieve the goal by pursuing three aims. (i) Optimize the next generation of dengue
NS4B inhibitor. We have developed a comprehensive medicinal chemistry optimization strategy to improve the
compound properties. (ii) Conduct preclinical characterization and deliver an IND-ready next-generation NS4B
inhibitor. (iii) Determine the mode-of-action and resistance potential of NITD-688. NS4B is a transmembrane
protein that participates in replication complex through interacting with other viral and host proteins. We will take
chemo-proteomic, biochemical, and cellular approaches to define the mechanism of compound inhibition. Such
knowledge can be applied to other membrane proteins for antiviral discovery.
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Discovery of next-generation dengue NS4B inhibitors
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批准号:10845865
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项目类别:
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资助金额:$20.37万
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财政年份:2022
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负责人:Christopher Sarko
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依托单位:
海外基金