© 1999 by Oxford University Press
Journal of the National Cancer Institute, Vol. 91, No. 14, 1211-1220,
July 21, 1999
© 1999 Oxford University Press
Potential Drugs Against Cervical Cancer: Zinc-Ejecting Inhibitors of the Human Papillomavirus Type 16 E6 Oncoprotein
Affiliations of authors: W. Beerheide, Y.-J. Tan, A. E.Ting (Screening for Novel Inhibitors Laboratory), H.-U. Bernard (Papillomavirus Biology Laboratory), A. Ganesan (Medicinal and Combinatorial Chemistry Laboratory), Institute of Molecular and Cell Biology, Singapore; W. G. Rice, Laboratory of Antiviral Drug Mechanisms, Science Applications International Corp., National Cancer Institute-Frederick Cancer Research and Development Center, Frederick, MD.
Correspondence to: Hans-Ulrich Bernard, Ph.D., Institute of Molecular and Cell Biology, 30 Medical Dr., Singapore 117609, Republic of Singapore (e-mail: mcbhub{at}imcb.nus.edu.sg).
BACKGROUND: The principal agent in the etiology of cervical cancer, i.e., human papillomavirus (HPV) type 16, encodes three oncoproteins, E5, E6, and E7. Structural and mutational studies have identified two potential zinc-finger domains as critical for E6 protein function. We investigated several assays to identify and characterize compounds that interfere with the binding of zinc to E6. METHODS: Thirty-six compounds were selected on the basis of their structure, which would facilitate their participation in sulfhydryl residue-specific redox reactions, and were tested for their ability to release zinc from E6 protein. The zinc-ejecting compounds were then tested for their ability to inhibit E6 binding to E6-associated protein (E6AP) and E6-binding protein (E6BP), two coactivators of E6-mediated cellular transformation. The binding of E6 to E6BP and E6AP was measured by use of surface plasmon resonance (a technique that monitors molecular interactions by measuring changes in refractive index) and by use of in vitro translation assays. The compounds were also tested for their effects on the viability of HPV-containing cell lines. RESULTS: Nine of the 36 tested compounds ejected zinc from E6. Two of the nine compounds inhibited the interaction of E6 with E6AP and E6BP, and one of these two, 4,4'-dithiodimorpholine, selectively inhibited cell viability and induced higher levels of p53 protein (associated with the induction of apoptosis [programmed cell death]) in tumorigenic HPV-containing cells. CONCLUSION: We have described assay systems to identify compounds, such as 4,4'-dithiodimorpholine, that can potentially interfere with the biology and pathology of HPV. These assay systems may be useful in the development of drugs against cervical cancer, genital warts, and asymptomatic infections by genital HPVs.
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