权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Small-Molecule Covalent E6 Antagonists for Treatment of HPV Infection

小分子共价 E6 拮抗剂治疗 HPV 感染

基本信息

批准号：
10397131
负责人：
ELLIOT J. ANDROPHY
金额：
$ 64.51万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-01 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10397131
关键词：
Affinity Algorithms Alkynes Apoptosis Applications Grants Binding Binding Sites Biochemical Biological Biological Assay Cancer cell line Carcinoma in Situ Cell Culture Techniques Cell Line Cell Proliferation Cell Survival Cell model Cells Cervical Charge Clinical Trials Complex Computing Methodologies Crystallization Cysteine DNA Data Docking Drug Design Episome Epithelial Epithelial Cells Evaluation Exhibits FDA approved Funding Genome Goals Grant Growth HPV-High Risk Human Papillomavirus Human papilloma virus infection Human papillomavirus 16 Human papillomavirus 18 In Vitro Infection Interferometry Kinetics Maintenance Malignant - descriptor Malignant Neoplasms Malignant neoplasm of anus Malignant neoplasm of cervix uteri Mass Spectrum Analysis Mediating Methods Modification Molecular Neoplasm Metastasis Oncogenic Oropharyngeal Parents Pathology Peptides Persons Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacology Positioning Attribute Prevention Process Property Proteins Reaction Research Personnel Resolution Roentgen Rays Series Serine Site Specificity Structure Surface TP53 gene Techniques Testing Time Topical application Tumor Suppressor Proteins UBE3A gene Viral Genome Viral Proteins Virus Replication Work X-Ray Crystallography adduct antagonist base cancer cell cell killing cellular targeting chemical synthesis covalent bond design expectation first-in-human high risk improved infection risk inhibitor insight interdisciplinary approach malignant oropharynx neoplasm novel preclinical evaluation predictive modeling premalignant prevent protein protein interaction reaction rate recruit scaffold screening senescence small molecule small molecule libraries structural biology tumor progression ubiquitin ligase

项目摘要

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.

摘要