Small molecule inhibitors of the LEDGF site of human immunodeficiency virus integrase identified by fragment screening and structure based design.
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.
CSIRO Materials, Science and Engineering, Parkville, Victoria, Australia. tom.peat@csiro.au
Thomas S
TS
Peat
David I
DI
Rhodes
Nick
N
Vandegraaff
Giang
G
Le
Jessica A
JA
Smith
Lisa J
LJ
Clark
Eric D
ED
Jones
Jonathan A V
JA
Coates
Neeranat
N
Thienthong
Janet
J
Newman
Olan
O
Dolezal
Roger
R
Mulder
John H
JH
Ryan
G Paul
GP
Savage
Craig L
CL
Francis
John J
JJ
Deadman
D001665:Binding Sites; D002460:Cell Line; D018360:Crystallography, X-Ray; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006678:HIV / Q000187:drug effects / Q000201:enzymology*; D019427:HIV Integrase / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D055767:Immobilized Proteins / Q000737:chemistry / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D008958:Models, Molecular; D010446:Peptide Fragments / Q000032:analysis*; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D020349:Surface Plasmon Resonance
D004791:Enzyme Inhibitors; D055767:Immobilized Proteins; D036341:Intercellular Signaling Peptides and Proteins; D010446:Peptide Fragments; D054852:Small Molecule Libraries; C119380:lens epithelium-derived growth factor; D019427:HIV Integrase