Abstract
A fragment-based screen against human immunodeficiency virus type 1 (HIV) integrase led to a number of compounds that bound to the lens epithelium derived growth factor (LEDGF) binding site of the integrase catalytic core domain. We determined the crystallographic structures of complexes of the HIV integrase catalytic core domain for 10 of these compounds and quantitated the binding by surface plasmon resonance. We demonstrate that the compounds inhibit the interaction of LEDGF with HIV integrase in a proximity AlphaScreen assay, an assay for the LEDGF enhancement of HIV integrase strand transfer and in a cell based assay. The compounds identified represent a potential framework for the development of a new series of HIV integrase inhibitors that do not bind to the catalytic site of the enzyme.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Binding Sites
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Cell Line
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Crystallography, X-Ray
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Drug Design*
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacology*
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HIV / drug effects
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HIV / enzymology*
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HIV Integrase / chemistry*
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HIV Integrase / metabolism
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Humans
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Immobilized Proteins / chemistry
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Immobilized Proteins / metabolism
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Intercellular Signaling Peptides and Proteins / metabolism*
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Models, Molecular
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Peptide Fragments / analysis*
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Small Molecule Libraries / chemistry
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Small Molecule Libraries / pharmacology*
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Structure-Activity Relationship
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Surface Plasmon Resonance
Substances
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Enzyme Inhibitors
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Immobilized Proteins
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Intercellular Signaling Peptides and Proteins
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Peptide Fragments
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Small Molecule Libraries
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lens epithelium-derived growth factor
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HIV Integrase
Associated data
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PDB/3ZSO
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PDB/3ZSQ
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PDB/3ZSR
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PDB/3ZSV
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PDB/3ZSW
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PDB/3ZSX
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PDB/3ZSY
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PDB/3ZSZ
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PDB/3ZT0
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PDB/3ZT1
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PDB/3ZT2
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PDB/3ZT3
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PDB/3ZT4