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NS4B抑制剂。我们目前有一起泛登革热
血清型NS4B抑制剂NITD-688正在进行I期临床试验。临床前研究结果表明有两种潜在的风险
可能会威胁到这种化合物的进一步发展。因此,我们将开发一种第二代化合物来
减轻债务。我们将通过追求三个目标来实现这一目标。(一)优化下一代登革热
NS4B抑制剂。我们制定了全面的药物化学优化策略,以提高
复合属性。(Ii)进行临床前鉴定并提供可供IND使用的下一代NS4B
抑制剂。(3)测定NITD-688的作用模式和抗性电位。NS4B是一种跨膜蛋白
通过与其他病毒和宿主蛋白相互作用而参与复制复合体的蛋白质。我们会带上
用化学蛋白质组学、生化和细胞学的方法来确定化合物抑制的机制。是这样的
这些知识可以应用于其他膜蛋白,用于抗病毒的发现。
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:
-
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