Binding inhibitors of the bacterial sliding clamp by design

Gene Wijffels; Wynona M. Johnson; Aaron J. Oakley; Kathleen Turner; V. Chandana Epa; Susan J. Briscoe; Mitchell Polley; Andris J. Liepa; Albert Hofmann; Jens Buchardt; Caspar Christensen; Pavel Prosselkov; Brian P. Dalrymple; Paul F. Alewood; Philip A. Jennings; Nicholas E. Dixon; David A. Winkler

doi:10.1021/jm2004333

Binding inhibitors of the bacterial sliding clamp by design

Gene Wijffels^*, Wynona M. Johnson, Aaron J. Oakley, Kathleen Turner, V. Chandana Epa, Susan J. Briscoe, Mitchell Polley, Andris J. Liepa, Albert Hofmann, Jens Buchardt, Caspar Christensen, Pavel Prosselkov, Brian P. Dalrymple, Paul F. Alewood, Philip A. Jennings, Nicholas E. Dixon, David A. Winkler

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

39 Citations (Scopus)

Abstract

The bacterial replisome is a target for the development of new antibiotics to combat drug resistant strains. The β₂ 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 β₂ 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-β₂ interaction at low micromolar concentrations. We report the crystal structure of the complex containing one of these inhibitors, a biphenyl oxime, bound to β₂, as a starting point for further inhibitor design.

Original language	English
Pages (from-to)	4831-4838
Number of pages	8
Journal	Journal of Medicinal Chemistry
Volume	54
Issue number	13
DOIs	https://doi.org/10.1021/jm2004333
Publication status	Published - 14 Jul 2011

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Wijffels, G., Johnson, W. M., Oakley, A. J., Turner, K., Epa, V. C., 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. https://doi.org/10.1021/jm2004333

@article{0abbd2d9e7574af4b071356128639765,

title = "Binding inhibitors of the bacterial sliding clamp by design",

abstract = "The bacterial replisome is a target for the development of new antibiotics to combat drug resistant strains. The β2 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 β2 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-β2 interaction at low micromolar concentrations. We report the crystal structure of the complex containing one of these inhibitors, a biphenyl oxime, bound to β2, as a starting point for further inhibitor design.",

author = "Gene Wijffels and Johnson, {Wynona M.} and Oakley, {Aaron J.} and Kathleen Turner and Epa, {V. Chandana} and Briscoe, {Susan J.} and Mitchell Polley and Liepa, {Andris J.} and Albert Hofmann and Jens Buchardt and Caspar Christensen and Pavel Prosselkov and Dalrymple, {Brian P.} and Alewood, {Paul F.} and Jennings, {Philip A.} and Dixon, {Nicholas E.} and Winkler, {David A.}",

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Wijffels, G, Johnson, WM, Oakley, AJ, Turner, K, Epa, VC, Briscoe, SJ, Polley, M, Liepa, AJ, Hofmann, A, Buchardt, J, Christensen, C, Prosselkov, P, Dalrymple, BP, Alewood, PF, Jennings, PA, Dixon, NE & Winkler, DA 2011, 'Binding inhibitors of the bacterial sliding clamp by design', Journal of Medicinal Chemistry, vol. 54, no. 13, pp. 4831-4838. https://doi.org/10.1021/jm2004333

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AU - Wijffels, Gene

AU - Johnson, Wynona M.

AU - Oakley, Aaron J.

AU - Turner, Kathleen

AU - Epa, V. Chandana

AU - Briscoe, Susan J.

AU - Polley, Mitchell

AU - Liepa, Andris J.

AU - Hofmann, Albert

AU - Buchardt, Jens

AU - Christensen, Caspar

AU - Prosselkov, Pavel

AU - Dalrymple, Brian P.

AU - Alewood, Paul F.

AU - Jennings, Philip A.

AU - Dixon, Nicholas E.

AU - Winkler, David A.

PY - 2011/7/14

Y1 - 2011/7/14

N2 - The bacterial replisome is a target for the development of new antibiotics to combat drug resistant strains. The β2 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 β2 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-β2 interaction at low micromolar concentrations. We report the crystal structure of the complex containing one of these inhibitors, a biphenyl oxime, bound to β2, as a starting point for further inhibitor design.

AB - The bacterial replisome is a target for the development of new antibiotics to combat drug resistant strains. The β2 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 β2 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-β2 interaction at low micromolar concentrations. We report the crystal structure of the complex containing one of these inhibitors, a biphenyl oxime, bound to β2, as a starting point for further inhibitor design.

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DO - 10.1021/jm2004333

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SN - 0022-2623

VL - 54

SP - 4831

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JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 13

ER -

Binding inhibitors of the bacterial sliding clamp by design

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