Anhydrotetracycline-peptide conjugates as representatives for ligand-based transactivating systems.
Bioconjugates of anhydrotetracycline and minimal activation sequences (VP1, VP2) derived from the Herpes simplex virus protein VP16 were synthesized. Different ligation strategies were applied and the resulting molecules tested in HeLa cells expressing the reverse transactivator rtTA-S3 for activity. The data clearly demonstrate that the atc-peptide conjugates are able to penetrate the cell membrane. Furthermore, binding to and induction of rtTA-S3 were detected. Structure-activity relationships indicated that the biological activity of the atc-peptide strongly depends on the specific linker used. The N-terminally linked oxime derivative 10 proved excellent activity when the increase of luciferace activity indicated a transcriptional activation substantially exceeding the inducing properties of anhydrotetracycline.
Lochner
Susanne
S
Department of Chemistry and Pharmacy, Emil Fischer Center, Chair of Medicinal Chemistry, Friedrich Alexander University, Erlangen, Germany.
Einsiedel
Juergen
J
Schaefer
Gesa
G
Berens
Christian
C
Hillen
Wolfgang
W
Gmeiner
Peter
P
D000595:Amino Acid Sequence; D006367:HeLa Cells; D017405:Herpes Simplex Virus Protein Vmw65 / Q000737:chemistry*; D006801:Humans; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D012097:Repressor Proteins / Q000378:metabolism*; D018139:Simplexvirus / Q000737:chemistry*; D013752:Tetracycline / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D015533:Transcriptional Activation / Q000187:drug effects
D017405:Herpes Simplex Virus Protein Vmw65; D010455:Peptides; D012097:Repressor Proteins; C034811:tetracycline resistance-encoding transposon repressor protein; D013752:Tetracycline