Department of Medicine
Cyclin-Dependent Kinase Inhibitor p21; Drug 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
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.
DOI of Published Version
PLoS One. 2013 Dec 23;8(12):e84506. doi: 10.1371/journal.pone.0084506. Link to article on publisher's site
Cherry, Jonathan J.; Rietz, Anne; Malinkevich, Anna; Liu, Yuqi; Xie, Meng; Bartolowits, Matthew; Davisson, V. Jo; Baleja, James D.; and Androphy, Elliot J., "Structure based identification and characterization of flavonoids that disrupt human papillomavirus-16 E6 function" (2013). University of Massachusetts Medical School Faculty Publications. 446.
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