Identification of inhibitors to papillomavirus type 16 E6 protein based on three-dimensional structures of interacting proteins.
Human papillomaviruses (HPV) cause cutaneous and genital warts. A subset of HPV types is associated with a high-risk for progression to malignancy. The E6 protein from the high-risk HPV types represents an attractive target for intervention because of its roles in viral propagation and cellular transformation. E6 functions in part by interaction with human cellular proteins, several of which possess a helical E6-binding motif. The role for each amino acid in this motif for binding E6 has been tested through structure determination and site-directed mutagenesis. These structural and molecular biological approaches defined the spatial geometry of functional groups necessary for binding to E6. This E6-binding information (the E6-binding pharmacophore) was transferred into a three-dimensional query format suitable for computational screening of large chemical databases. Compounds were identified and tested using in vitro and cell culture-based assays. Several compounds selectively inhibited E6 interaction with the E6-binding protein E6AP and interfered with the ability of E6 to promote p53 degradation. Such compounds provide leads for the development of new pharmacologic agents to treat papillomavirus infections and their associated cancers.
Baleja
James D
JD
Department of Biochemistry, Tufts University School of Medicine, 136 Harrison Ave., Boston, MA 02111, USA. jim.baleja@tufts.edu
Cherry
Jonathan J
JJ
Liu
Zhiguo
Z
Gao
Hua
H
Nicklaus
Marc C
MC
Voigt
Johannes H
JH
Chen
Jason J
JJ
Androphy
Elliot J
EJ
D000998:Antiviral Agents / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D015195:Drug Design; D009856:Oncogene Proteins, Viral / Q000737:chemistry* / Q000378:metabolism; D027383:Papillomaviridae; D011485:Protein Binding; D012097:Repressor Proteins / Q000737:chemistry* / Q000378:metabolism; D016335:Zinc Fingers
D000998:Antiviral Agents; C068651:E6 protein, Human papillomavirus type 16; D009856:Oncogene Proteins, Viral; D012097:Repressor Proteins