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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI038001-06
Application #
6373476
Study Section
Virology Study Section (VR)
Program Officer
Tseng, Christopher K
Project Start
1995-07-01
Project End
2005-08-31
Budget Start
2001-09-01
Budget End
2002-08-31
Support Year
6
Fiscal Year
2001
Total Cost
$359,554
Indirect Cost
Name
Tufts University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02111
Liu, Yuqi; Baleja, James D (2008) Structure and function of the papillomavirus E6 protein and its interacting proteins. Front Biosci 13:121-34
Liu, Yuqi; Henry, Gillian D; Hegde, Rashmi S et al. (2007) Solution structure of the hDlg/SAP97 PDZ2 domain and its mechanism of interaction with HPV-18 papillomavirus E6 protein. Biochemistry 46:10864-74
Baleja, James D; Cherry, Jonathan J; Liu, Zhiguo et al. (2006) Identification of inhibitors to papillomavirus type 16 E6 protein based on three-dimensional structures of interacting proteins. Antiviral Res 72:49-59
Liu, Yuqi; Liu, Zhiguo; Androphy, Elliot et al. (2004) Design and characterization of helical peptides that inhibit the E6 protein of papillomavirus. Biochemistry 43:7421-31
Be, X; Hong, Y; Wei, J et al. (2001) Solution structure determination and mutational analysis of the papillomavirus E6 interacting peptide of E6AP. Biochemistry 40:1293-9
Peng, Y C; Breiding, D E; Sverdrup, F et al. (2000) AMF-1/Gps2 binds p300 and enhances its interaction with papillomavirus E2 proteins. J Virol 74:5872-9
Moscufo, N; Sverdrup, F; Breiding, D E et al. (1999) Two distinct regions of the BPV1 E1 replication protein interact with the activation domain of E2. Virus Res 65:141-54
Baleja, J D; Thanabal, V; Wagner, G (1997) Refined solution structure of the DNA-binding domain of GAL4 and use of 3J(113Cd,1H) in structure determination. J Biomol NMR 10:397-401