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Small-Molecule Covalent E6 Antagonists for Treatment of HPV Infection

Small-Molecule Covalent E6 Antagonists for Treatment of HPV Infection
小分子共价 E6 拮抗剂治疗 HPV 感染
批准号:
10610388
负责人:
ELLIOT J. ANDROPHY
金额:
$60.72万
依托单位国家:
美国
项目类别:
财政年份:
2021
资助国家:
美国
项目状态:
未结题
起止时间:
2021-05-01 至 2026-04-30
关键词:
AffinityAlgorithmsAlkynesApoptosisApplications GrantsBindingBinding SitesBiochemicalBiologicalBiological AssayCancer cell lineCarcinoma in SituCell Culture TechniquesCell LineCell ProliferationCell SurvivalCell modelCellsCervicalChargeClinical TrialsComplexComputing MethodologiesCrystallizationCrystallographyCysteineDNADataDockingDrug DesignEpisomeEpithelial CellsEpitheliumEvaluationExhibitsFDA approvedFundingGenomeGoalsGrantGrowthHPV-High RiskHuman PapillomavirusHuman papilloma virus infectionHuman papillomavirus 18In VitroInduction of ApoptosisInfectionInterferometryKineticsMaintenanceMalignant - descriptorMalignant NeoplasmsMalignant neoplasm of anusMalignant neoplasm of cervix uteriMass Spectrum AnalysisMediatingMethodsModificationMolecularNeoplasm MetastasisOncogenicOropharyngealPapillomavirus Transforming Protein E6ParentsPathologyPeptidesPersonsPharmaceutical ChemistryPharmaceutical PreparationsPositioning AttributePreventionProcessPropertyProteinsReactionResearch PersonnelResolutionRiskRoentgen RaysSeriesSerineSiteSpecificityStructureSurfaceTP53 geneTechniquesTestingTimeTopical applicationTumor Suppressor ProteinsUBE3A geneViralViral GenomeViral ProteinsVirus ReplicationWorkX-Ray Crystallographyadductantagonistcancer cellcell killingcellular targetingchemical synthesiscovalent bonddesigndrug isolationdrug-like compoundexpectationfirst-in-humanhigh riskimprovedinhibitorinsightinterdisciplinary approachmalignant oropharynx neoplasmmeternovelpharmacologicpreclinical evaluationpredictive modelingpremalignantpreventprotein protein interactionreaction raterecruitscaffoldscreeningsenescencesmall moleculesmall molecule librariesstructural biologytumor progressionubiquitin ligase

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中文摘要
翻译
摘要 人类乳头瘤病毒(HPV)的高危类型,如16型(HPV-16),在大多数HPV中被发现- 宫颈、肛门和口咽上皮的相关癌前病变和恶性病变。这个 E6蛋白是病毒复制和致癌转化的细胞模型所必需的。我们假设 与E6结合并与其形成共价键的小分子将拮抗E6的功能,包括 结合泛素连接酶E6AP的能力和P53的募集以促进蛋白酶体的降解。基于结构的 在设计和合成衍生物之后进行的计算机筛选导致了一系列 与HPV-16E6蛋白相互作用并形成共价键并抑制两者的小分子 E6·E6AP体外联合作用与E6介导的细胞内P53降解依赖于时间和浓度 与E6结合的四个小分子的质谱学和高分辨共晶结构得到证实 这个假说。这项拨款申请的目的是扩大我们发现的新型E6抑制剂 使用计算、生化、结晶学、药理学和细胞生物学分析来确定化学类型 增强活力和活力。在目标1中,我们将预测建模算法与这些X射线相结合 结构以指示在E6·E6AP界面上进行额外残基的修饰。在目标2中,稳健 生化技术将表征这些抑制剂的结合和反应动力学。X射线 结晶学将被应用于解析与HPV E6结合的新化合物的原子坐标,从而 指导目标1中提出的基于结构的计算设计。在目标3中,我们测试了小分子E6 利用HPV-16恢复P53水平和诱导细胞凋亡的特异性抑制物 表达癌细胞系。将研究E6与细胞的直接接触,并可能偏离目标 细胞蛋白质将被鉴定出来。我们的预期是,将有2-3名类似药物的候选人选择性地出现 抑制HPV-16E6功能,表现出亚微摩尔IC50活性和合适的药理性质 在人类临床试验中迈向第一。
英文摘要
ABSTRACT “High-risk” human papillomavirus (HPV) types such as 16 (HPV-16) are identified in the majority of HPV- associated pre-malignant and malignant pathologies of cervical, anogenital, and oropharyngeal epithelia. The E6 protein is essential for viral replication and cellular models of oncogenic transformation. We hypothesized that small molecules that bind to and form a covalent bond with E6 will antagonize its functions, including the ability to bind the ubiquitin ligase E6AP and recruitment of p53 for proteasomal degradation. Structure-based computational screening followed by design and synthesis of derivatives led to the identification of a series of small molecules that interact with and form a covalent bond to the HPV-16 E6 protein and inhibit both E6•E6AP association in vitro and E6-mediated p53 degradation in cells. Time- and concentration-dependent mass spectrometry and high resolution co-crystal structures of four small molecules bound to E6 confirmed this hypothesis. The objective of this grant application is to extend our discovery of novel E6 inhibitor chemotypes using computational, biochemical, crystallographic, pharmacologic and cell biological assays to increase potency and activity. In Aim 1, we combine predictive modeling algorithms with these X-ray structures to instruct modifications that engage additional residues at the E6•E6AP interface. In Aim 2, robust biochemical techniques will characterize the binding and reaction kinetics of these inhibitors. X-ray crystallography will be applied to resolve atomic coordinates of new compounds bound to HPV E6 and thereby guide the structure-based computational designs proposed in Aim 1. In Aim 3, we test the small-molecule E6 inhibitors for their specific ability to restore p53 levels, and induce apoptosis ord senescence using HPV-16 expressing cancer cell lines. Direct engagement of E6 in cells will be investigated and potential off-target cellular proteins will be identified. Our expectation is that 2-3 drug-like candidates will emerge that selectively inhibit HPV-16 E6 function and exhibit sub-micromolar IC50 activity and suitable pharmacologic properties to advance toward first in human clinical trials.
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Small Molecule E6 Inhibitors to Treat Oropharyngeal Cancers Caused by HPV Infections
  • 批准号:
    10484043
  • 项目类别:
  • 资助金额:
    $27.58万
  • 财政年份:
    2022
  • 负责人:
    ELLIOT J. ANDROPHY
  • 依托单位:
Small Molecule E6 Inhibitors to Treat Dysplasia Caused by HPV Infections
  • 批准号:
    10390563
  • 项目类别:
  • 资助金额:
    $29.85万
  • 财政年份:
    2022
  • 负责人:
    ELLIOT J. ANDROPHY
  • 依托单位:
Development of a mouse model to test HPV Antiviral compounds
Small-Molecule Covalent E6 Antagonists for Treatment of HPV Infection
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