Navegar

Colección

Datos Estadísticas

Artículo

Este artículo es de Acceso Abierto y puede ser descargado en su versión final desde nuestro repositorio
Consulte el artículo en la página del editor
Consulte la política de Acceso Abierto del editor

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. Methodology/Principal Findings: 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/Significance: 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. © 2011 Wetzler et al.

Registro:

Documento: Artículo
Título:New human papilloma virus E2 transcription factor mimics: A tripyrrole-peptide conjugate with tight and specific DNA-recognition
Autor:Wetzler, D.E.; Comin, M.J.; Krajewski, K.; Gallo, M.
Filiación:Department of Biological Chemistry, FCEN University of Buenos Aires, Buenos Aires, Argentina
Center for Research and Development in Chemistry, INTI, Buenos Aires, Argentina
Department of Biochemistry and Biophysics, School of Medicine, University of North Carolina, Chapel Hill, NC, United States
Fundación Instituto Leloir, Buenos Aires, Argentina
Palabras clave:distamycin A; DNA; peptide; protein E2; transcription factor; unclassified drug; antivirus agent; biomimetic material; distamycin A; DNA binding protein; E2 protein, Human papillomavirus type 16; oncoprotein; peptide fragment; pyrrole derivative; virus DNA; alpha helix; article; circular dichroism; computer model; conjugation; DNA synthesis; gel mobility shift assay; Human papillomavirus type 16; nonhuman; nuclear magnetic resonance spectroscopy; protein DNA binding; protein interaction; protein structure; amino acid sequence; chemical structure; chemistry; enzyme specificity; genetics; Human papillomavirus type 16; metabolism; molecular genetics; nucleotide sequence; papillomavirus infection; physiology; protein secondary structure; synthesis; Human papillomavirus; Human papillomavirus type 16; Amino Acid Sequence; Antiviral Agents; Base Sequence; Biomimetic Materials; Distamycins; DNA, Viral; DNA-Binding Proteins; Human papillomavirus 16; Models, Molecular; Molecular Sequence Data; Oncogene Proteins, Viral; Papillomavirus Infections; Peptide Fragments; Protein Structure, Secondary; Pyrroles; Substrate Specificity
Año:2011
Volumen:6
Número:7
DOI: http://dx.doi.org/10.1371/journal.pone.0022409
Título revista:PLoS ONE
Título revista abreviado:PLoS ONE
ISSN:19326203
CAS:DNA, 9007-49-2; distamycin A, 13696-04-3, 39389-47-4, 636-47-5; Antiviral Agents; DNA, Viral; DNA-Binding Proteins; Distamycins; E2 protein, Human papillomavirus type 16; Oncogene Proteins, Viral; Peptide Fragments; Pyrroles; stallimycin, 636-47-5
PDF:https://bibliotecadigital.exactas.uba.ar/download/paper/paper_19326203_v6_n7_p_Wetzler.pdf
Registro:https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_19326203_v6_n7_p_Wetzler

Referencias:

  • Muñoz, N., Bosch, F.X., de Sanjose, S., Herrero, R., Castellsague, X., Epidemiologic classification of human papillomavirus types associated with cervical cancer (2003) N Engl J Med, 348, pp. 518-527
  • Su, J.H., Wu, A., Scotney, E., Ma, B., Monie, A., Immunotherapy for cervical cancer: Research status and clinical potential (2010) BioDrugs, 24, pp. 109-129
  • Thierry, F., Transcriptional regulation of the papillomavirus oncogenes by cellular and viral transcription factors in cervical carcinoma (2009) Virology, 384, pp. 375-379
  • Dell, G., Gaston, K., Human papillomaviruses and their role in cervical cancer (2001) Cell Mol Life Sci, 58, pp. 1923-1942
  • Kim, S.S., Tam, J.K., Wang, A.F., Hegde, R.S., The structural basis of DNA target discrimination by papillomavirus E2 proteins (2000) J Biol Chem, 275, pp. 31245-31254
  • Koh, J.T., Zheng, J., The new biomimetic chemistry: artificial transcription factors (2007) ACS Chem Biol, 2, pp. 599-601
  • Vazquez, M.E., Caamano, A.M., Mascarenas, J.L., From transcription factors to designed sequence-specific DNA-binding peptides (2003) Chem Soc Rev, 32, pp. 338-349
  • Hegde, R.S., The papillomavirus E2 proteins: structure, function, and biology (2002) Annu Rev Biophys Biomol Struct, 31, pp. 343-360
  • Ferreiro, D.U., Lima, L.M., Nadra, A.D., Alonso, L.G., Goldbaum, F.A., Distinctive cognate sequence discrimination, bound DNA conformation, and binding modes in the E2 C-terminal domains from prototype human and bovine papillomaviruses (2000) Biochemistry, 39, pp. 14692-14701
  • Cicero, D.O., Nadra, A.D., Eliseo, T., Dellarole, M., Paci, M., Structural and thermodynamic basis for the enhanced transcriptional control by the human papillomavirus strain-16 E2 protein (2006) Biochemistry, 45, pp. 6551-6560
  • Wetzler, D.E., Gallo, M., Melis, R., Eliseo, T., Nadra, A.D., A strained DNA binding helix is conserved for site recognition, folding nucleation, and conformational modulation (2009) Biopolymers, 91, pp. 432-443
  • Faber-Barata, J., Mohana-Borges, R., Lima, L.M., Specificity in DNA recognition by a peptide from papillomavirus E2 protein (2006) FEBS Lett, 580, pp. 1919-1924
  • Vazquez, M.E., Caamano, A.M., Martinez-Costas, J., Castedo, L., Mascarenas, J.L., Design and Synthesis of a Peptide That Binds Specific DNA Sequences through Simultaneous Interaction in the Major and in the Minor Groove (2001) Angew Chem Int Ed Engl, 40, pp. 4723-4725
  • Blanco, J.B., Vazquez, M.E., Castedo, L., Mascarenas, J.L., Sequence-specific DNA recognition by monomeric bZIP basic regions equipped with a tripyrrole unit on the N-terminal side. Towards the development of synthetic mimics of Skn-1 (2005) Chembiochem, 6, pp. 2173-2176
  • Blanco, J.B., Vazquez, O., Martinez-Costas, J., Castedo, L., Mascarenas, J.L., High affinity, sequence specific DNA binding by synthetic tripyrrole-peptide conjugates (2005) Chemistry, 11, pp. 4171-4178
  • Chen, F.M., Sha, F., Circular dichroic and kinetic differentiation of DNA binding modes of distamycin (1998) Biochemistry, 37, pp. 11143-11151
  • Uytterhoeven, K., Sponer, J., van Meervelt, L., Two 1: 1 binding modes for distamycin in the minor groove of d(GGCCAATTGG) (2002) Eur J Biochem, 269, pp. 2868-2877
  • Marion, D., Wuthrich, K., Application of phase sensitive two-dimensional correlated spectroscopy (COSY) for measurements of 1H-1H spin-spin coupling constants in proteins (1983) Biochem Biophys Res Commun, 113, pp. 967-974
  • Delaglio, F., Grzesiek, S., Vuister, G.W., Zhu, G., Pfeifer, J., NMRPipe: a multidimensional spectral processing system based on UNIX pipes (1995) J Biomol NMR, 6, pp. 277-293
  • Johnson, B.A., Using NMRView to visualize and analyze the NMR spectra of macromolecules (2004) Methods Mol Biol, 278, pp. 313-352
  • Lyu, P.C., Sherman, J.C., Chen, A., Kallenbach, N.R., Alpha-helix stabilization by natural and unnatural amino acids with alkyl side chains (1991) Proc Natl Acad Sci U S A, 88, pp. 5317-5320
  • Ferreiro, D.U., Dellarole, M., Nadra, A.D., de Prat-Gay, G., Free energy contributions to direct readout of a DNA sequence (2005) J Biol Chem, 280, pp. 32480-32484
  • Vazquez, O., Vazquez, M.E., Blanco, J.B., Castedo, L., Mascarenas, J.L., Specific DNA recognition by a synthetic, monomeric Cys2His2 zinc-finger peptide conjugated to a minor-groove binder (2007) Angew Chem Int Ed Engl, 46, pp. 6886-6890
  • Vazquez, O., Blanco-Canosa, J.B., Vazquez, M.E., Martinez-Costas, J., Castedo, L., Efficient DNA binding and nuclear uptake by distamycin derivatives conjugated to octa-arginine sequences (2008) Chembiochem, 9, pp. 2822-2829
  • Dellarole, M., Sanchez, I.E., Freire, E., de Prat-Gay, G., Increased stability and DNA site discrimination of "single chain" variants of the dimeric beta-barrel DNA binding domain of the human papillomavirus E2 transcriptional regulator (2007) Biochemistry, 46, pp. 12441-12450
  • Hill, J.J., Fluorescence approaches to study of protein-nucleic acid complexation (1997) Methods Enzymol, 278, pp. 390-416

Citas:

---------- APA ----------
Wetzler, D.E., Comin, M.J., Krajewski, K. & Gallo, M. (2011) . New human papilloma virus E2 transcription factor mimics: A tripyrrole-peptide conjugate with tight and specific DNA-recognition. PLoS ONE, 6(7).
http://dx.doi.org/10.1371/journal.pone.0022409
---------- CHICAGO ----------
Wetzler, D.E., Comin, M.J., Krajewski, K., Gallo, M. "New human papilloma virus E2 transcription factor mimics: A tripyrrole-peptide conjugate with tight and specific DNA-recognition" . PLoS ONE 6, no. 7 (2011).
http://dx.doi.org/10.1371/journal.pone.0022409
---------- MLA ----------
Wetzler, D.E., Comin, M.J., Krajewski, K., Gallo, M. "New human papilloma virus E2 transcription factor mimics: A tripyrrole-peptide conjugate with tight and specific DNA-recognition" . PLoS ONE, vol. 6, no. 7, 2011.
http://dx.doi.org/10.1371/journal.pone.0022409
---------- VANCOUVER ----------
Wetzler, D.E., Comin, M.J., Krajewski, K., Gallo, M. New human papilloma virus E2 transcription factor mimics: A tripyrrole-peptide conjugate with tight and specific DNA-recognition. PLoS ONE. 2011;6(7).
http://dx.doi.org/10.1371/journal.pone.0022409