Structure based identification and characterization of flavonoids that disrupt human papillomavirus-16 E6 function

Jonathan J. Cherry, Anne Rietz, Anna Malinkevich, Yuqi Liu, Meng Xie, Matthew Bartolowits, V. Jo Davisson, James D. Baleja, Elliot Androphy

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

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 p21Cip1/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 α-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.

Original languageEnglish
Article numbere84506
JournalPLoS One
Volume8
Issue number12
DOIs
StatePublished - Dec 23 2013

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Human papillomavirus 16
Flavonoids
flavonoids
Papillomaviridae
Proteins
proteins
Cells
Assays
uterine cervical neoplasms
virus replication
Uterine Cervical Neoplasms
assays
Flavones
Luteolin
Tumor Suppressor Protein p53
Ubiquitin-Protein Ligases
Papillomavirus Infections

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Structure based identification and characterization of flavonoids that disrupt human papillomavirus-16 E6 function. / Cherry, Jonathan J.; Rietz, Anne; Malinkevich, Anna; Liu, Yuqi; Xie, Meng; Bartolowits, Matthew; Davisson, V. Jo; Baleja, James D.; Androphy, Elliot.

In: PLoS One, Vol. 8, No. 12, e84506, 23.12.2013.

Research output: Contribution to journalArticle

Cherry, JJ, Rietz, A, Malinkevich, A, Liu, Y, Xie, M, Bartolowits, M, Davisson, VJ, Baleja, JD & Androphy, E 2013, 'Structure based identification and characterization of flavonoids that disrupt human papillomavirus-16 E6 function', PLoS One, vol. 8, no. 12, e84506. https://doi.org/10.1371/journal.pone.0084506
Cherry, Jonathan J. ; Rietz, Anne ; Malinkevich, Anna ; Liu, Yuqi ; Xie, Meng ; Bartolowits, Matthew ; Davisson, V. Jo ; Baleja, James D. ; Androphy, Elliot. / Structure based identification and characterization of flavonoids that disrupt human papillomavirus-16 E6 function. In: PLoS One. 2013 ; Vol. 8, No. 12.
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