Identification of novel inhibitors targeting entry of human cytomegalovirus
Identification of novel inhibitors targeting entry of human cytomegalovirus
批准号:
8403863
负责人:
Domenico Tortorella
金额:
$4.24万
依托单位国家:
美国
项目类别:
财政年份:
2012
资助国家:
美国
项目状态:
已结题
起止时间:
2012-07-15 至 2014-06-30
关键词:
Acquired Immunodeficiency SyndromeAdverse effectsAffectAnemiaAttenuatedAutoimmune DiseasesAutoimmune ProcessBiological AssayCancer PatientCardiovascular DiseasesChemicalsClinicalCongenital AbnormalityCytomegalovirusCytomegalovirus InfectionsDNA biosynthesisDNA-Directed DNA PolymeraseDeveloped CountriesDiseaseDrug resistanceElderlyFailureFibroblastsFunctional disorderGanciclovirGene ExpressionGenerationsGenomicsGoalsGrantHIVHourHumanImmediate-Early GenesImmediate-Early ProteinsImmunocompromised HostImmunosuppressive AgentsIndividualInfantInfectionLeadLife Cycle StagesMalignant NeoplasmsMolecularMolecular ProfilingMorbidity - disease rateNeutropeniaNewborn InfantNuclearOne-Step dentin bonding systemOrganOrgan TransplantationPatientsPharmaceutical PreparationsPhasePopulationProcessProteinsReagentRegimenReplication LicensingReportingRetinitisRiskSeveritiesSignal TransductionSignaling ProteinTherapeuticThrombocytopeniaToxic effectTransplant RecipientsTransplantationUnited StatesUnited States National Institutes of HealthValganciclovirValidationVariantViralViral GenesViral GenomeViral Load resultViral ProteinsVirionVirusVirus DiseasesVirus Replicationalternative treatmentdrug resistant virushigh riskhigh throughput screeningimmune functioninhibitor/antagonistlatent persistent infectionmortalityneonatenovelnovel therapeuticsolder patientpathogenpatient populationpreventsmall moleculestandard of careviral DNA
中文摘要
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英文摘要
DESCRIPTION (provided by applicant): Human cytomegalovirus (HCMV) is an opportunistic pathogen with the ability to establish and maintain a lifelong relationship with its host, a persistent state termed latency. Primary infections and reactivation of latent HCMV results in a high viral load in patients with inadequate immune function commonly results in uncontrolled virus replication, and multi-organ disease and dysfunction. In fact, HCMV significantly contributes to morbidity and mortality in immunocompromised individuals such as newborns, organ transplant recipients, AIDS patients, cancer patients, patients with cardiovascular diseases, autoimmune disease patients, as well as the elderly. HCMV is the leading cause of birth defects affecting 1-4% of newborns in developed countries and significantly contributes to transplant failure. HCMV also increases the severity of cardiovascular diseases, autoimmune diseases, and various cancers. Current therapy against HCMV targets the viral DNA polymerase, but induces severe side effects (e.g. thrombocytopenia) and drug-resistant viral strains upon prolonged treatment. Our central hypothesis is that inhibiting HCMV proliferation by targeting diverse steps of the HCMV life cycle would effectively limit HCMV-associated diseases. Thus, we propose to identify novel therapeutics that inhibit the early steps of HCMV infection utilizing a HCMV variant that expresses a viral protein (immediate-early protein 2) fused to yellow fluorescent protein. A high-content screen will be performed at the NIH Chemical Genomics Core to identify compounds that block the early steps of virus infection. High- throughput secondary assays will be performed to identify lead compounds through their validation in a diverse high-content screen, an effective concentration in the nanomolar range and low toxicity. Also, tertiary assays will define the mode of action of the lead compounds. The discovery of anti-HCMV reagents against the early phase of infection represents a novel class of compounds that will target different proteins than the current therapeutics with the objective o attenuating HCMV proliferation and HCMV-associated diseases in immunocompromised individuals.
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科研奖励(0)
会议论文
Human CMV monoclonal antibodies as therapeutics to inhibit virus infection and dissemination
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批准号:10867639
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项目类别:
-
资助金额:$68.39万
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财政年份:2023
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负责人:Domenico Tortorella
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依托单位:
Identification of human cytomegalovirus life cycle stage-specific therapeutics
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批准号:10443755
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项目类别:
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资助金额:$39.62万
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财政年份:2019
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负责人:Domenico Tortorella
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依托单位:
Identification of human cytomegalovirus life cycle stage-specific therapeutics
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批准号:9981622
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项目类别:
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资助金额:$39.62万
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财政年份:2019
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负责人:Domenico Tortorella
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依托单位:
Identification of human cytomegalovirus life cycle stage-specific therapeutics
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批准号:9755701
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项目类别:
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资助金额:$41.36万
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财政年份:2019
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负责人:Domenico Tortorella
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依托单位:
Identification of human cytomegalovirus life cycle stage-specific therapeutics
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批准号:10192497
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项目类别:
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资助金额:$39.62万
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财政年份:2019
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负责人:Domenico Tortorella
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依托单位:
Functional screening for neutralizing antibodies targeting CMV entry factors
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批准号:8722813
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项目类别:
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资助金额:$25.43万
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财政年份:2014
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负责人:Domenico Tortorella
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依托单位:
Assay development to discover therapeutics against human cytomegalovirus
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批准号:8667395
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项目类别:
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资助金额:$33.71万
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财政年份:2013
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负责人:Domenico Tortorella
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依托单位:
Assay development to discover therapeutics against human cytomegalovirus
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批准号:8853789
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项目类别:
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资助金额:$33.47万
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财政年份:2013
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负责人:Domenico Tortorella
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依托单位:
Assay development to discover therapeutics against human cytomegalovirus
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批准号:8505769
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项目类别:
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资助金额:$28.98万
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财政年份:2013
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负责人:Domenico Tortorella
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依托单位:
Identification of novel inhibitors targeting entry of human cytomegalovirus
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批准号:8507708
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项目类别:
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资助金额:$4.11万
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财政年份:2012
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负责人:Domenico Tortorella
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依托单位:
Identification of Inhibitors that Stabilize ER Degradation Substrates
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批准号:8286199
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项目类别:
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资助金额:$4.24万
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财政年份:2011
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负责人:Domenico Tortorella
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依托单位:
Identification of Inhibitors that Stabilize ER Degradation Substrates
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批准号:8138920
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项目类别:
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资助金额:$4.24万
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财政年份:2011
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负责人:Domenico Tortorella
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依托单位:
Down-regulation of MHC class l molecules by HCMV US2
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批准号:7846496
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项目类别:
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资助金额:$3.39万
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财政年份:2009
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负责人:Domenico Tortorella
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依托单位:
Down-regulation of MHC class l molecules by HCMV US2
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批准号:7382429
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项目类别:
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资助金额:$5.05万
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财政年份:2005
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负责人:Domenico Tortorella
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依托单位:
Down-regulation of MHC class l molecules by HCMV US2
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批准号:6922522
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项目类别:
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资助金额:$28.82万
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财政年份:2005
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负责人:Domenico Tortorella
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依托单位:
Down-regulation of MHC class l molecules by HCMV US2
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批准号:7568866
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项目类别:
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资助金额:$38.11万
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财政年份:2005
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负责人:Domenico Tortorella
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依托单位:
Down-regulation of MHC class l molecules by HCMV US2
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批准号:7039054
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项目类别:
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资助金额:$33.1万
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财政年份:2005
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负责人:Domenico Tortorella
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依托单位:
Down-regulation of MHC class l molecules by HCMV US2
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批准号:7333257
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项目类别:
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资助金额:$38.11万
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财政年份:2005
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负责人:Domenico Tortorella
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依托单位:
Down-regulation of MHC class l molecules by HCMV US2
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批准号:7188041
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项目类别:
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资助金额:$32.14万
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财政年份:2005
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负责人:Domenico Tortorella
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依托单位:
Luminescent assay:ER dislocation inhibitors (RMI)
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批准号:6880187
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项目类别:
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资助金额:$8.48万
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财政年份:2004
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负责人:Domenico Tortorella
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依托单位:
海外基金