Crystal Structures of Novel Allosteric Peptide Inhibitors of HIV Integrase Identify New Interactions at the LEDGF Binding Site

• Published in: Chembiochem : a European journal of chemical biology Vol. 12; no. 15; pp. 2311 - 2315
• Main Authors: Rhodes, David I., Peat, Thomas S., Vandegraaff, Nick, Jeevarajah, Dharshini, Newman, Janet, Martyn, John, Coates, Jonathan A. V., Ede, Nicholas J., Rea, Philip, Deadman, John J.
• Format: Journal Article
• Language: English
• Published: Weinheim WILEY-VCH Verlag 17-10-2011; WILEY‐VCH Verlag
• Subjects: Amino Acid Sequence; Binding Sites; co-crystal structures; Crystallography, X-Ray; cyclic peptides; HIV Infections - virology; HIV Integrase - chemistry; HIV Integrase - metabolism; HIV Integrase Inhibitors - chemistry; HIV Integrase Inhibitors - pharmacology; HIV-1 - chemistry; HIV-1 - enzymology; HIV-1 integrase; Humans; Hydrogen Bonding; inhibitors; LEDGF; Molecular Docking Simulation; Peptides, Cyclic - chemistry; Peptides, Cyclic - pharmacology
• ISSN: 1439-4227; 1439-7633
• DOI: 10.1002/cbic.201100350

An optimised method of solution cyclisation gave us access to a series of peptides including SLKIDNLD (2). We investigated the crystallographic complexes of the HIV integrase (HIV‐IN) catalytic core domain with 13 of the peptides and identified multiple interactions at the binding site, including hydrogen bonds with residues Thr125 and Gln95, that have not previously been described as being accessible within the binding site. We show that the peptides inhibit the interaction of lens epithelium‐derived growth factor (LEDGF) with HIV‐IN in a proximity AlphaScreen assay and in an assay for the LEDGF enhancement of HIV‐IN strand transfer. The interactions identified represent a potential framework for the development of new HIV‐IN inhibitors.
H‐bonds uncovered: Solution cyclisation has given access to a series of 13 peptides. Upon investigating their complexes with the HIV integrase catalytic core domain (the bound peptides are shown superimposed), we identified multiple, previously undescribed interactions at the binding site. These interactions represent a potential framework for developing new HIV‐integrase inhibitors.