Cyclic Hexapeptide Mimics of the LEDGF Integrase Recognition Loop in Complex with HIV‐1 Integrase |
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| Authors: | Dr Susan E Northfield Dr Jerome Wielens Dr Stephen J Headey Billy J Williams‐Noonan Dr Mark Mulcair Prof Martin J Scanlon Prof Michael W Parker Prof Philip E Thompson Dr David K Chalmers |
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| Affiliation: | 1. Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Parkville, Victoria, Australia;2. ACRF Rational Drug Discovery Centre, St. Vincent's Institute of Medical Research, Fitzroy, Victoria, Australia;3. Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Victoria, Australia |
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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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| Keywords: | crystallography HIV-1 integrase LEDGF NMR peptide mimetics |
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