Fig. (5) Inhibition of the E6-E6AP interaction. (A) Simplified model of how the HPV oncogenes E6 and E7 stimulate cellular proliferation. Binding of E7 to pRb leads to the release and activation of the E2F transcription factors and drives differentiating keratinocytes into S-phase. This unscheduled DNA synthesis triggers a p53-dependent cell cycle arrest and apoptotic response that is prevented by E6, through its interaction with E6AP, and targets p53 for proteasomal degradation. (B) Schematic representation of E6AP. E6AP possesses several well-characterized functional domains including a HECT domain (yellow) and an E6-binding site (E6BS). The amino acid sequence corresponding to the E6BS is indicated and the three conserved leucine residues, Leu-9, Leu-12, Leu-13, are highlighted in orange. (C) NMR structure of the E6AP peptide showing the positions of the three leucine residues, Leu-9, Leu-12, and Leu-13 important for E6 binding are colored in orange (PDB accession number 1EQX [152]). (D) Structure of Compound 9, an E6-E6AP inhibitor used as a starting point for the synthesis of other closely related inhibitors of E6 activity.