title: New human papilloma virus E2 transcription factor mimics: a tripyrrole-peptide conjugate with tight and specific DNA-recognition.
abstract: BACKGROUND
  Human papillomavirus (HPV) is the main causative agent of cervical cancer, particularly high risk strains such us HPV-16, -18 and -31. The viral encoded E2 protein acts as a transcriptional modulator and exerts a key role in viral DNA replication. Thus, E2 constitutes an attractive target for developing antiviral agents. E2 is a homodimeric protein that interacts with the DNA target through an α-helix of each monomer. However, a peptide corresponding to the DNA recognition helix of HPV-16 E2 binds DNA with lower affinity than its full-length DNA binding domain. Therefore, in an attempt to promote the DNA binding of the isolated peptide, we have designed a conjugate compound of the E2 α-helix peptide and a derivative of the antibiotic distamycin, which involves simultaneous minor- and major-groove interactions.
  
  
  RESULTS
  An E2 α-helix peptide-distamycin conjugate was designed and synthesized. It was characterized by NMR and CD spectroscopy, and its DNA binding properties were investigated by CD, DNA melting and gel shift experiments. The coupling of E2 peptide with distamycin does not affect its structural properties. The conjugate improves significantly the affinity of the peptide for specific DNA. In addition, stoichiometric amounts of specific DNA increase meaningfully the helical population of the peptide. The conjugate enhances the DNA binding constant 50-fold, maintaining its specificity.
  
  
  CONCLUSIONS
  These results demonstrate that peptide-distamycin conjugates are a promising tool to obtain compounds that bind the E2 target DNA-sequences with remarkable affinity and suggest that a bipartite major/minor groove binding scaffold can be a useful approach for therapeutic treatment of HPV infection.
authors.affiliation: Department of Biological Chemistry, FCEN, University of Buenos Aires, Buenos Aires, Argentina.
authors.forename: Diana E
authors.initials: DE
authors.lastname: Wetzler
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Comin
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Krajewski
authors.forename: Mariana
authors.initials: M
authors.lastname: Gallo
mesh_terms: D000595:Amino Acid Sequence; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use; D001483:Base Sequence; D040761:Biomimetic Materials / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism* / Q000627:therapeutic use; D004279:DNA, Viral / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000737:chemistry*; D004214:Distamycins / Q000737:chemistry; D052162:Human papillomavirus 16 / Q000502:physiology; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009856:Oncogene Proteins, Viral / Q000737:chemistry*; D030361:Papillomavirus Infections / Q000188:drug therapy; D010446:Peptide Fragments / Q000737:chemistry*; D017433:Protein Structure, Secondary; D011758:Pyrroles / Q000737:chemistry*; D013379:Substrate Specificity
chemical_list: D000998:Antiviral Agents; D004279:DNA, Viral; D004268:DNA-Binding Proteins; D004214:Distamycins; C054855:E2 protein, Human papillomavirus type 16; D009856:Oncogene Proteins, Viral; D010446:Peptide Fragments; D011758:Pyrroles; C030000:stallimycin