Cyclic Hexapeptide Mimics of the LEDGF Integrase Recognition Loop in Complex with HIV-1 Integrase

Susan E Northfield, Jerome Wielens, Stephen J Headey, Billy J Williams-Noonan, Mark Mulcair, Martin Scanlon, Michael W Parker, Philip E Thompson, David K Chalmers

Research output: Contribution to journalArticleResearchpeer-review

Abstract

The p75 splice variant of lens epithelium-derived growth factor (LEDGF) is a 75 kDa protein, which is recruited by the human immunodeficiency virus (HIV) to tether the pre-integration complex to the host chromatin and promote integration of proviral DNA into the host genome. We designed a series of small cyclic peptides that are structural mimics of the LEDGF binding domain, which interact with integrase as potential binding inhibitors. Herein we present the X-ray crystal structures, NMR studies, SPR analysis, and conformational studies of four cyclic peptides bound to the HIV-1 integrase core domain. Although the X-ray studies show that the peptides closely mimic the LEDGF binding loop, the measured affinities of the peptides are in the low millimolar range. Computational analysis using conformational searching and free energy calculations suggest that the low affinity of the peptides is due to mismatch between the low-energy solution and bound conformations.

Original languageEnglish
Pages (from-to)1555-1565
Number of pages11
JournalChemMedChem
Volume13
Issue number15
DOIs
Publication statusPublished - 10 Aug 2018

Keywords

  • crystallography
  • HIV-1 integrase
  • LEDGF
  • NMR
  • peptide mimetics

Cite this

Northfield, Susan E ; Wielens, Jerome ; Headey, Stephen J ; Williams-Noonan, Billy J ; Mulcair, Mark ; Scanlon, Martin ; Parker, Michael W ; Thompson, Philip E ; Chalmers, David K. / Cyclic Hexapeptide Mimics of the LEDGF Integrase Recognition Loop in Complex with HIV-1 Integrase. In: ChemMedChem. 2018 ; Vol. 13, No. 15. pp. 1555-1565.
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abstract = "The p75 splice variant of lens epithelium-derived growth factor (LEDGF) is a 75 kDa protein, which is recruited by the human immunodeficiency virus (HIV) to tether the pre-integration complex to the host chromatin and promote integration of proviral DNA into the host genome. We designed a series of small cyclic peptides that are structural mimics of the LEDGF binding domain, which interact with integrase as potential binding inhibitors. Herein we present the X-ray crystal structures, NMR studies, SPR analysis, and conformational studies of four cyclic peptides bound to the HIV-1 integrase core domain. Although the X-ray studies show that the peptides closely mimic the LEDGF binding loop, the measured affinities of the peptides are in the low millimolar range. Computational analysis using conformational searching and free energy calculations suggest that the low affinity of the peptides is due to mismatch between the low-energy solution and bound conformations.",
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Northfield, SE, Wielens, J, Headey, SJ, Williams-Noonan, BJ, Mulcair, M, Scanlon, M, Parker, MW, Thompson, PE & Chalmers, DK 2018, 'Cyclic Hexapeptide Mimics of the LEDGF Integrase Recognition Loop in Complex with HIV-1 Integrase' ChemMedChem, vol. 13, no. 15, pp. 1555-1565. https://doi.org/10.1002/cmdc.201800129

Cyclic Hexapeptide Mimics of the LEDGF Integrase Recognition Loop in Complex with HIV-1 Integrase. / Northfield, Susan E; Wielens, Jerome; Headey, Stephen J; Williams-Noonan, Billy J; Mulcair, Mark; Scanlon, Martin; Parker, Michael W; Thompson, Philip E; Chalmers, David K.

In: ChemMedChem, Vol. 13, No. 15, 10.08.2018, p. 1555-1565.

Research output: Contribution to journalArticleResearchpeer-review

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Northfield SE, Wielens J, Headey SJ, Williams-Noonan BJ, Mulcair M, Scanlon M et al. Cyclic Hexapeptide Mimics of the LEDGF Integrase Recognition Loop in Complex with HIV-1 Integrase. ChemMedChem. 2018 Aug 10;13(15):1555-1565. https://doi.org/10.1002/cmdc.201800129