Inactivation of the human papillomavirus-16 E6 oncoprotein by organic disulfides.
We are investigating compounds that could be useful in the treatment of neoplastic lesions of the cervix by acting on the oncoprotein E6 of human papillomavirus-16. The E6 protein contains two potential zinc-binding domains that are required for most of its functions. We have published tests that measure (i) the release of zinc ions after chemical alteration of the cysteine groups of these zinc-binding domains (TSQ assay), (ii) the interaction of E6 with the cellular proteins E6AP and E6BP (BIACORE assay), and (iii) the viability of tumor cell lines that require the continuous expression of HPV oncoproteins (WST1 assay). Based on these tests, we identified 4.4'-dithiodimorpholine as a potential lead compound. In this study we examined whether the dithiobisamine moiety of 4,4'-dithiodimorpholine may be an important molecular prerequisite for further drug development in this system. We have evaluated 59 new substances including organic disulfides and those containing the dithiobisamine moiety, as well as structural analogues. The compounds with significant reactivity in all three assays were observed only for dithiobisamine derivatives with saturated cyclic amines and aryl substituted piperazines. The identity of these substances suggests that the N-S-S-N moiety is necessary but not sufficient for reactivity in our assays, and that dithiobisamine based substances are useful as lead compounds that target the cysteine groups of HPV-16 E6 zinc fingers.
Beerheide
W
W
Drug Screen Development Laboratory, Institute of Molecular and Cell Biology, Singapore. w.beerheide@DKFZ-Heidelberg.de
Sim
M M
MM
Tan
Y J
YJ
Bernard
H U
HU
Ting
A E
AE
D000998:Antiviral Agents / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology* / Q000627:therapeutic use; D015374:Biosensing Techniques; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D003545:Cysteine / Q000378:metabolism; D004220:Disulfides / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology* / Q000627:therapeutic use; D006571:Heterocyclic Compounds / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D008025:Ligases / Q000378:metabolism; D015394:Molecular Structure; D009025:Morpholines / Q000737:chemistry / Q000378:metabolism; D009856:Oncogene Proteins, Viral / Q000737:chemistry* / Q000378:metabolism*; D027383:Papillomaviridae / Q000187:drug effects; D030361:Papillomavirus Infections / Q000188:drug therapy; D011083:Polycyclic Compounds / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D011485:Protein Binding / Q000187:drug effects; D012097:Repressor Proteins; D014407:Tumor Cells, Cultured; D044767:Ubiquitin-Protein Ligases; D015032:Zinc / Q000378:metabolism
D000998:Antiviral Agents; D002135:Calcium-Binding Proteins; D004220:Disulfides; C068651:E6 protein, Human papillomavirus type 16; D006571:Heterocyclic Compounds; D009025:Morpholines; D009856:Oncogene Proteins, Viral; D011083:Polycyclic Compounds; C088393:RCN2 protein, human; D012097:Repressor Proteins; D044767:Ubiquitin-Protein Ligases; D008025:Ligases; D015032:Zinc; D003545:Cysteine