Journal article
Cyclic Hexapeptide Mimics of the LEDGF Integrase Recognition Loop in Complex with HIV-1 Integrase
SE Northfield, J Wielens, SJ Headey, BJ Williams-Noonan, M Mulcair, MJ Scanlon, MW Parker, PE Thompson, DK Chalmers
Chemmedchem | WILEY-V C H VERLAG GMBH | Published : 2018
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..
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Awarded by Australian Cancer Research Foundation
Funding Acknowledgements
The integrase core domain construct used for NMR was a kind gift of Ad Bax (NIH, Maryland, USA). We also thank the MX beamline staff for their help at the Australian synchrotron. This work was supported by the Australian Research Council Linkage project (LP0775192), the Australian Synchrotron Research Program and the Australian Cancer Research Foundation to M.W.P. M.W.P. is an ARC Federation Fellow and National Health Medical Research Council Honorary Fellow. We acknowledge computational resources and technical support provided by the National Computational Infrastructure (NCI), and Multi-modal Australian ScienceS Imaging and Visualisation Environment (MASSIVE) through grant y96. We also acknowledge the provision of an Australian Post-graduate Award to S.N.