Structure based identification and characterization of flavonoids that disrupt human papillomavirus-16 E6 function
Authors
Cherry, Jonathan J.Rietz, Anne
Malinkevich, Anna
Liu, Yuqi
Xie, Meng
Bartolowits, Matthew
Davisson, V. Jo
Baleja, James D.
Androphy, Elliot J.
UMass Chan Affiliations
Department of MedicineDocument Type
Journal ArticlePublication Date
2013-12-23Keywords
Cyclin-Dependent Kinase Inhibitor p21Drug Discovery
Female
Flavonoids
High-Throughput Screening Assays
Human papillomavirus 16
Humans
Luteolin
*Models, Molecular
Molecular Structure
Oncogene Proteins, Viral
Protein Binding
Repressor Proteins
Tumor Suppressor Protein p53
Ubiquitin-Protein Ligases
Uterine Cervical Neoplasms
Cell Biology
Infectious Disease
Neoplasms
Oncology
Virology
Virus Diseases
Women's Health
Metadata
Show full item recordAbstract
Expression and function of the human papillomavirus (HPV) early protein 6 (E6) is necessary for viral replication and oncogenesis in cervical cancers. HPV E6 targets the tumor suppressor protein p53 for degradation. To achieve this, "high-risk" HPV E6 proteins bind to and modify the target specificity of the ubiquitin ligase E6AP (E6 associated protein). This E6-dependent loss of p53 enables the virus to bypass host cell defenses and facilitates virally induced activation of the cell cycle progression during viral replication. Disruption of the interaction between E6 and E6AP and stabilization of p53 should decrease viability and proliferation of HPV positive cells. A new in vitro high-throughput binding assay was developed to assay binding between HPV-16 E6 and E6AP and to identify compounds that inhibit this interaction. The compound luteolin emerged from the screen and a library of novel flavones based on its structure was synthesized and characterized using this in vitro binding assay. The compounds identified in this study disrupt the E6/E6AP interaction, increase the levels of p53 and p21(Cip1/Waf1), and decrease proliferation of HPV positive cell lines. The new class of flavonoid E6 inhibitors displays a high degree of specificity for HPV positive cells. Docking analyses suggest that these compounds bind in a hydrophobic pocket at the interface between E6 and E6AP and mimic the leucines in the conserved alpha-helical motif of E6AP. The activity and specificity of these compounds represent a promising new lead for development as an antiviral therapy in the treatment of HPV infection and cervical cancer.Source
PLoS One. 2013 Dec 23;8(12):e84506. doi: 10.1371/journal.pone.0084506. Link to article on publisher's siteDOI
10.1371/journal.pone.0084506Permanent Link to this Item
http://hdl.handle.net/20.500.14038/30200PubMed ID
24376816Related Resources
Link to Article in PubMedDistribution License
http://creativecommons.org/licenses/by/4.0/ae974a485f413a2113503eed53cd6c53
10.1371/journal.pone.0084506
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Except where otherwise noted, this item's license is described as http://creativecommons.org/licenses/by/4.0/
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