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Binding inhibitors of the bacterial sliding clamp by design

Journal Article


Abstract


  • The bacterial replisome is a target for the development of new antibiotics to combat drug resistant strains. The β 2 sliding clamp is an essential component of the replicative machinery, providing a platform for recruitment and function of other replisomal components and ensuring polymerase processivity during DNA replication and repair. A single binding region of the clamp is utilized by its binding partners, which all contain conserved binding motifs. The C-terminal Leu and Phe residues of these motifs are integral to the binding interaction. We acquired three-dimensional structural information on the binding site in β 2 by a study of the binding of modified peptides. Development of a three-dimensional pharmacophore based on the C-terminal dipeptide of the motif enabled identification of compounds that on further development inhibited α-β 2 interaction at low micromolar concentrations. We report the crystal structure of the complex containing one of these inhibitors, a biphenyl oxime, bound to β 2, as a starting point for further inhibitor design. © Published 2011 by the American Chemical Society.

Authors


  •   Wijffels, Gene (external author)
  •   Johnson, W M. (external author)
  •   Oakley, Aaron J.
  •   Turner, Kathleen (external author)
  •   Epa, V C. (external author)
  •   Briscoe, S J. (external author)
  •   Polley, M (external author)
  •   Liepa, A J. (external author)
  •   Hofmann, A (external author)
  •   Buchardt, J (external author)
  •   Christensen, C (external author)
  •   Prosselkov, Pavel (external author)
  •   Dalrymple, B (external author)
  •   Alewood, Paul F. (external author)
  •   Jennings, P A. (external author)
  •   Dixon, Nicholas E.
  •   Winkler, D A. (external author)

Publication Date


  • 2011

Citation


  • Wijffels, G., Johnson, W. M., Oakley, A. J., Turner, K., Epa, V. Chandana., Briscoe, S. J., Polley, M., Liepa, A. J., Hofmann, A., Buchardt, J., Christensen, C., Prosselkov, P., Dalrymple, B. P., Alewood, P. F., Jennings, P. A., Dixon, N. E. & Winkler, D. A. (2011). Binding inhibitors of the bacterial sliding clamp by design. Journal of Medicinal Chemistry, 54 (13), 4831-4838.

Scopus Eid


  • 2-s2.0-79960180851

Ro Metadata Url


  • http://ro.uow.edu.au/scipapers/5261

Number Of Pages


  • 7

Start Page


  • 4831

End Page


  • 4838

Volume


  • 54

Issue


  • 13

Abstract


  • The bacterial replisome is a target for the development of new antibiotics to combat drug resistant strains. The β 2 sliding clamp is an essential component of the replicative machinery, providing a platform for recruitment and function of other replisomal components and ensuring polymerase processivity during DNA replication and repair. A single binding region of the clamp is utilized by its binding partners, which all contain conserved binding motifs. The C-terminal Leu and Phe residues of these motifs are integral to the binding interaction. We acquired three-dimensional structural information on the binding site in β 2 by a study of the binding of modified peptides. Development of a three-dimensional pharmacophore based on the C-terminal dipeptide of the motif enabled identification of compounds that on further development inhibited α-β 2 interaction at low micromolar concentrations. We report the crystal structure of the complex containing one of these inhibitors, a biphenyl oxime, bound to β 2, as a starting point for further inhibitor design. © Published 2011 by the American Chemical Society.

Authors


  •   Wijffels, Gene (external author)
  •   Johnson, W M. (external author)
  •   Oakley, Aaron J.
  •   Turner, Kathleen (external author)
  •   Epa, V C. (external author)
  •   Briscoe, S J. (external author)
  •   Polley, M (external author)
  •   Liepa, A J. (external author)
  •   Hofmann, A (external author)
  •   Buchardt, J (external author)
  •   Christensen, C (external author)
  •   Prosselkov, Pavel (external author)
  •   Dalrymple, B (external author)
  •   Alewood, Paul F. (external author)
  •   Jennings, P A. (external author)
  •   Dixon, Nicholas E.
  •   Winkler, D A. (external author)

Publication Date


  • 2011

Citation


  • Wijffels, G., Johnson, W. M., Oakley, A. J., Turner, K., Epa, V. Chandana., Briscoe, S. J., Polley, M., Liepa, A. J., Hofmann, A., Buchardt, J., Christensen, C., Prosselkov, P., Dalrymple, B. P., Alewood, P. F., Jennings, P. A., Dixon, N. E. & Winkler, D. A. (2011). Binding inhibitors of the bacterial sliding clamp by design. Journal of Medicinal Chemistry, 54 (13), 4831-4838.

Scopus Eid


  • 2-s2.0-79960180851

Ro Metadata Url


  • http://ro.uow.edu.au/scipapers/5261

Number Of Pages


  • 7

Start Page


  • 4831

End Page


  • 4838

Volume


  • 54

Issue


  • 13