In this revised competitive grant application Dr. Baleja describes studies designed to identify small molecule inhibitors of the E6 oncoprotein of human papillomaviruses associated with cervical cancer. The identification of these inhibitors shall be based upon structural information obtained for small peptides from E6AP and E6BP that mediate the binding of these cellular factors to E6. Proof of principle studies are now provided in the revised grant application as is additional NMR based structural information regarding the E6AP and E6BP peptides. Small molecules will be characterized for their capacity to interfere with E6 function in vitro, in tissue culture, and ultimately in animal models.
A second aim i s refocused on trying to modify tatE2 fusion peptides that have proven of moderate value in inhibiting the function of the E2 transcriptional transactivator. These modifications are designed to improve DNA binding activity and alter dimerization properties so as to increase the effectiveness of the fusion protein in inhibiting E2TA function and in repressing transcription of the E6 and E7 genes.
