Structure of cytomegalovirus nuclease, UL98
巨细胞病毒核酸酶 UL98 的结构
基本信息
- 批准号:9086246
- 负责人:
- 金额:$ 7.63万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2015
- 资助国家:美国
- 起止时间:2015-06-15 至 2017-11-30
- 项目状态:已结题
- 来源:
- 关键词:Acquired Immunodeficiency SyndromeActive SitesAntiviral AgentsAttenuatedBiochemicalBiological AssayBlindnessCessation of lifeCidofovirCollaborationsComplementComplexComputer SimulationCongenital AbnormalityCrystallizationCytomegalovirusCytomegalovirus InfectionsDNADNA PackagingDNA StructureDNA biosynthesisDNA-Directed DNA PolymeraseDeoxyribonucleasesDevelopmentDiseaseDissectionDose-LimitingEscherichia coliEvaluationFetusFoscarnetFutureGanciclovirGeneticGenetic RecombinationGoalsGrowthHIVHealthHerpesviridaeHerpesvirus 1Homologous ProteinHomology ModelingHumanHuman Herpesvirus 4Human Herpesvirus 8ImmuneIn VitroLaboratoriesLeadLigandsMental RetardationMessenger RNAMolecularMutagenesisMutationNewborn InfantNucleotidesOutcomePatientsPharmaceutical PreparationsPharmacologic SubstancePlayPregnancyProteinsPulmonary InflammationRecombinant ProteinsRecombinantsResearch PersonnelRetinitisRibonucleasesRoentgen RaysRoleStructureT-LymphocyteTechniquesTherapeuticToxic effectTranslationsTransplant RecipientsTransplantationViralViral ProteinsVirusVirus ReplicationX ray diffraction analysisX-Ray Diffractionbasedeafnessdesigndrug developmentdrug discoveryendoexonucleaseexperiencehearing impairmentin uteroinhibitor/antagonistinsightmembermutantnovelnucleasepathogenpreventprotein complexprotein expressionprototyperepairedsmall moleculesmall molecule inhibitorviral DNAviral alkaline nucleaseviral resistance
项目摘要
DESCRIPTION (provided by applicant): Human cytomegalovirus (CMV) is a herpes virus and prototype of the beta herpes virus subfamily. CMV causes pneumonitis, blindness, and death among transplant and AIDS patients, and mental retardation and hearing loss among newborns. There is a pressing need for development of new antiviral drugs to treat CMV infections. All herpes viruses encode an alkaline nuclease (AN) and ANs are among the most highly conserved herpes virus proteins. However, the roles that ANs play in virus replication are not well understood and differ between subfamilies. DNase activities of ANs from the alpha herpes virus subfamily are proposed to promote recombination or facilitate DNA packaging by removing branches or unusual structures from newly replicated viral DNA. In contrast, ANs from the gamma herpes virus subfamily have RNase activity and function to shut off host protein translation by degrading mRNAs. Whether beta herpes virus ANs serve similar roles or have functions unique to the beta herpes virus subfamily is not known. The current application is a well-established multi-investigator collaboration focused on defining the structure and biochemical activities of the CMV AN, UL98, understanding its mechanistic roles in CMV replication, and identifying small molecule inhibitors of UL98 to explore its potential as an antiviral target. Our initial studies used homology modeling to predict the UL98 active site and mutagenesis of E. coli-expressed UL98 to confirm the importance of active site residues for DNase activity. A UL98-null virus was constructed and found to be profoundly growth-attenuated, demonstrating that UL98 is critically important for CMV replication and suggesting that small molecule inhibitors of UL98 may have potent antiviral activity. In support of the latter atanyl blue PRL, an inhibitor of UL98 nuclease activity, has been shown to inhibit CMV replication. The current application has one aim: to determine crystal structures of wild type UL98 and two catalytically-deficient UL98 mutants, as well as UL98 complexed with DNA and with the inhibitor atanyl blue PRL. Comparison of the UL98 structure with existing structures of gamma herpes virus ANs will allow identification of structural features that are unique to each of these proteins. The UL98 structure may also suggest novel functional domains that will help guide the design of mutations to dissect UL98's biochemical activities and functional roles in replication. Importantly, the structure of UL98 complexed with the inhibitor atanyl blue PRL will provide valuable mechanistic and structural insights and will inform and enable structure-based identification of additional UL98 inhibitors. Such inhibitors will serve as pharmacological probes to complement and extend genetic and biochemical studies of UL98's functions and may provide important lead structures for antiviral development. These advances will enable expanded pursuit of UL98 as an antiviral target and may ultimately lead to novel antivirals for treating CMV infections.
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Martin K Safo其他文献
A Novel Direct Hemoglobin S Polymerization Inhibitor for the Treatment of Sickle Cell Disease - emIn Vivo/em Efficacy of Ilx-002 in Humanized Mice
一种用于治疗镰状细胞病的新型血红蛋白S直接聚合抑制剂——人源化小鼠体内Ilx-002的疗效
- DOI:
10.1182/blood-2024-202714 - 发表时间:
2024-11-05 - 期刊:
- 影响因子:23.100
- 作者:
Osheiza Abdulmalik;Kandace Gollomp;Veronica Bochenek;Conroy O Field;Mariana Macias;Benita Balogun;Salma Roland;Martin K Safo;Yan Zhang;Akua Donkor;Abdelsattar Omar;Moustafa El-Araby;David R. Light;Clark Brown;Andrew N Fleischman - 通讯作者:
Andrew N Fleischman
A Novel Direct Hemoglobin S Polymerization Inhibitor for the Treatment of Sickle Cell Disease - <em>In Vivo</em> Efficacy of Ilx-002 in Humanized Mice
- DOI:
10.1182/blood-2024-202714 - 发表时间:
2024-11-05 - 期刊:
- 影响因子:
- 作者:
Osheiza Abdulmalik;Kandace Gollomp;Veronica Bochenek;Conroy O Field;Mariana Macias;Benita Balogun;Salma Roland;Martin K Safo;Yan Zhang;Akua Donkor;Abdelsattar Omar;Moustafa El-Araby;David R. Light;Clark Brown;Andrew N Fleischman - 通讯作者:
Andrew N Fleischman
Martin K Safo的其他文献
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{{ truncateString('Martin K Safo', 18)}}的其他基金
Hemoglobin Modifiers for Sickle Cell Disease Therapy
用于镰状细胞病治疗的血红蛋白调节剂
- 批准号:
8776137 - 财政年份:2014
- 资助金额:
$ 7.63万 - 项目类别:
Hemoglobin Modifiers for Sickle Cell Disease Therapy
用于镰状细胞病治疗的血红蛋白调节剂
- 批准号:
9250636 - 财政年份:2014
- 资助金额:
$ 7.63万 - 项目类别:
Hemoglobin Modifiers for Sickle Cell Disease Therapy
用于镰状细胞病治疗的血红蛋白调节剂
- 批准号:
9053281 - 财政年份:2014
- 资助金额:
$ 7.63万 - 项目类别:
Hemoglobin Modifiers for Sickle Cell Disease Therapy
用于镰状细胞病治疗的血红蛋白调节剂
- 批准号:
9445715 - 财政年份:2014
- 资助金额:
$ 7.63万 - 项目类别:
Hemoglobin Modifiers for Sickle Cell Disease Therapy
用于镰状细胞病治疗的血红蛋白调节剂
- 批准号:
9147091 - 财政年份:2014
- 资助金额:
$ 7.63万 - 项目类别:
Rational Design of Novel Estrogen Receptor Antagonists
新型雌激素受体拮抗剂的合理设计
- 批准号:
7174671 - 财政年份:2004
- 资助金额:
$ 7.63万 - 项目类别:
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