Discovery and development of novel anti-HCMV agents targeting the UL89 terminase protein
发现和开发针对 UL89 终止酶蛋白的新型抗 HCMV 药物
基本信息
- 批准号:10534193
- 负责人:
- 金额:$ 65.45万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-01-25 至 2024-12-31
- 项目状态:已结题
- 来源:
- 关键词:ATP phosphohydrolaseAcquired Immunodeficiency SyndromeActive SitesAntiviral AgentsBindingBiochemicalBiochemistryBiological AssayBrain InjuriesCell Culture TechniquesCell SurvivalChemistryCidofovirClinicCollaborationsComplexCytomegalovirusCytomegalovirus InfectionsDNA PackagingDataDevelopmentDiseaseDrug KineticsDrug TargetingDrug resistanceEnzymesFDA approvedFetal DevelopmentFoscarnetFoundationsGanciclovirGenerationsGoalsHumanImmunocompromised HostIn VitroIndividualInfectious AgentInterventionInvestigationLibrariesMetalsMolecular TargetMorbidity - disease rateMutationMutation AnalysisNewborn InfantPatientsPharmaceutical ChemistryPharmaceutical PreparationsPolymeraseProdrugsProductionPropertyProphylactic treatmentProteinsPublishingResearchResistanceRoleSignal TransductionStructureTechniquesToxic effectTransplant RecipientsTransplantationUnited States Food and Drug AdministrationValganciclovirViralViral GenomeVirusVirus AssemblyVirus ReplicationWorkallograft rejectionanalogcostdrug candidateendonucleaseexperimental studyhearing impairmenthigh throughput screeningimmune system functionimprovedin vivoinhibitorinnovationinterdisciplinary approachmortalitynew therapeutic targetnovelnovel therapeuticspharmacophorepost-transplantpre-clinicalpreventresistant strainscaffoldscreeningside effectsmall moleculestandard of carestructural biologysuccesstargeted agentterminasetoolviral genomicsviral resistancevirologyvirtual screening
项目摘要
Project Summary/Abstract
Human cytomegalovirus (HCMV) infection in individuals lacking a fully functioning immune system, such as
newborns and transplant patients, can result in severe and debilitating consequences. The majority of the US
Food and Drug Administration approved anti-HCMV drugs target the viral polymerase and resistance to those
drugs has appeared. Therefore, anti-HCMV drugs from novel targets are needed for use in combination with,
or instead of, current polymerase inhibitors. The long-term goal of this proposal is to develop structurally novel
direct-acting antivirals against HCMV targeting aspects of virus replication outside of those for currently
approved drugs. Towards this end, a viral ATPase/endonuclease (pUL89) critically involved in viral genome
packaging and virus assembly has been chosen as a target for antiviral intervention. The objective of this
investigation is to identify, optimize and characterize pUL89 inhibitor scaffolds. To accomplish these goals,
the following specific aims will be pursued: 1. Develop and implement screening assays to identify pUL89 and
HCMV inhibitors. These assays include biochemical assays for pUL89 function as well as HCMV replication
assays in cell culture. 2. HCMV pUL89 inhibitor hit generation and optimization. Hit generation will center
around the focused screening of in-house synthetic small molecules and select compound libraries.
Confirmed hits will be optimized via analogue synthesis, iterative SAR and in vitro ADME assays to generate
potent inhibitors with favorable physicochemical properties. 3. Characterization of advanced inhibitors using
virological, structural and pharmacokinetic techniques. Optimized inhibitor binding to pUL89 will be analyzed
and refined using structural studies. Detailed virological experiments will be performed to characterize the
mechanism of action, verify the target of these inhibitors and document their ability to work with current FDA
approved drugs and against resistant virus. In addition, in vivo pharmacokinetic parameters of the optimized
inhibitors will be determined and used to improve drug-like properties. At the conclusion of the studies outlined
in this proposal, a better understanding of the mechanism of action and role of pUL89 endonuclease activity
in virus replication will be gained and multiple potent preclinical drug candidates targeting pUL89 will be
developed.
项目总结/文摘
项目成果
期刊论文数量(5)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Repurposing N-hydroxy thienopyrimidine-2,4-diones (HtPD) as inhibitors of human cytomegalovirus pUL89 endonuclease: Synthesis and biological characterization.
- DOI:10.1016/j.bioorg.2022.106198
- 发表时间:2022-12
- 期刊:
- 影响因子:5.1
- 作者:He T;Edwards TC;Majima R;Jung E;Kankanala J;Xie J;Geraghty RJ;Wang Z
- 通讯作者:Wang Z
Discovery of N-benzyl hydroxypyridone carboxamides as a novel and potent antiviral chemotype against human cytomegalovirus (HCMV).
- DOI:10.1016/j.apsb.2021.08.019
- 发表时间:2022-04
- 期刊:
- 影响因子:14.5
- 作者:Senaweera, Sameera;Edwards, Tiffany C.;Kankanala, Jayakanth;Wang, Yan;Sahani, Rajkumar Lalji;Xie, Jiashu;Geraghty, Robert J.;Wang, Zhengqiang
- 通讯作者:Wang, Zhengqiang
8-Hydroxy-1,6-naphthyridine-7-carboxamides as Inhibitors of Human Cytomegalovirus pUL89 Endonuclease.
8-羟基-1,6-萘吡啶-7-羧酰胺作为人类巨细胞病毒PUL89核酸内切酶的抑制剂。
- DOI:10.1002/cmdc.202200334
- 发表时间:2022-09-05
- 期刊:
- 影响因子:3.4
- 作者:Jung, Eunkyung;Majima, Ryuichi;Edwards, Tiffany C.;Soto-Acosta, Ruben;Geraghty, Robert J.;Wang, Zhengqiang
- 通讯作者:Wang, Zhengqiang
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Robert James Geraghty其他文献
Robert James Geraghty的其他文献
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{{ truncateString('Robert James Geraghty', 18)}}的其他基金
Discovery and development of novel anti-HCMV agents targeting the UL89 terminase protein
发现和开发针对 UL89 终止酶蛋白的新型抗 HCMV 药物
- 批准号:
10318943 - 财政年份:2019
- 资助金额:
$ 65.45万 - 项目类别:
Spread of HSV-1 mediated by the gD receptor nectin-1
gD 受体 nectin-1 介导的 HSV-1 传播
- 批准号:
6667357 - 财政年份:2002
- 资助金额:
$ 65.45万 - 项目类别:
Spread of HSV-1 mediated by the gD receptor nectin-1
gD 受体 nectin-1 介导的 HSV-1 传播
- 批准号:
6706949 - 财政年份:2002
- 资助金额:
$ 65.45万 - 项目类别:
Spread of HSV-1 mediated by the gD receptor nectin-1
gD 受体 nectin-1 介导的 HSV-1 传播
- 批准号:
6860144 - 财政年份:2002
- 资助金额:
$ 65.45万 - 项目类别:
Spread of HSV-1 mediated by the gD receptor nectin-1
gD 受体 nectin-1 介导的 HSV-1 传播
- 批准号:
7031532 - 财政年份:2002
- 资助金额:
$ 65.45万 - 项目类别:
Spread of HSV-1 mediated by the gD receptor nectin-1
gD 受体 nectin-1 介导的 HSV-1 传播
- 批准号:
6461587 - 财政年份:2002
- 资助金额:
$ 65.45万 - 项目类别:
PROTEIN INTERACTIONS IN HERPESVIRUS CELL FUSION
疱疹病毒细胞融合中的蛋白质相互作用
- 批准号:
2671615 - 财政年份:1998
- 资助金额:
$ 65.45万 - 项目类别:
PROTEIN INTERACTIONS IN HERPESVIRUS CELL FUSION
疱疹病毒细胞融合中的蛋白质相互作用
- 批准号:
2643308 - 财政年份:1997
- 资助金额:
$ 65.45万 - 项目类别:
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