Interaction of small molecule inhibitors of HIV-1 entry with CCR5.
The CC-chemokine receptor 5 (CCR5) is the major coreceptor for macrophage-tropic (R5) HIV-1 strains. Several small molecule inhibitors of CCR5 that block chemokine binding and HIV-1 entry are being evaluated as drug candidates. Here we define how CCR5 antagonists TAK-779, AD101 (SCH-350581) and SCH-C (SCH-351125), which inhibit HIV-1 entry, interact with CCR5. Using a mutagenesis approach in combination with a viral entry assay to provide a direct functional read out, we tested predictions based on a homology model of CCR5 and analyzed the functions of more than 30 amino acid residues. We find that a key set of aromatic and aliphatic residues serves as a hydrophobic core for the ligand binding pocket, while E283 is critical for high affinity interaction, most likely by acting as the counterion for a positively charged nitrogen atom common to all three inhibitors. These results provide a structural basis for understanding how specific antagonists interact with CCR5, and may be useful for the rational design of new, improved CCR5 ligands.
Laboratory of Molecular Biology and Biochemistry, The Rockefeller University, New York, NY 10021, USA. seiberc@mail.rockefeller.edu
Christoph
C
Seibert
Weiwen
W
Ying
Svetlana
S
Gavrilov
Fotini
F
Tsamis
Shawn E
SE
Kuhmann
Anandan
A
Palani
Jayaram R
JR
Tagat
John W
JW
Clader
Stuart W
SW
McCombie
Bahige M
BM
Baroudy
Steven O
SO
Smith
Tatjana
T
Dragic
John P
JP
Moore
Thomas P
TP
Sakmar
D000577:Amides / Q000378:metabolism; D001665:Binding Sites / Q000235:genetics; D002460:Cell Line; D003497:Cyclic N-Oxides / Q000378:metabolism; D023581:HIV Fusion Inhibitors / Q000378:metabolism*; D015497:HIV-1 / Q000254:growth & development; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D016297:Mutagenesis, Site-Directed; D010091:Oximes; D010880:Piperidines / Q000378:metabolism; D017433:Protein Structure, Secondary; D011725:Pyridines / Q000378:metabolism; D000644:Quaternary Ammonium Compounds / Q000378:metabolism; D019713:Receptors, CCR5 / Q000235:genetics / Q000378:metabolism*
D000577:Amides; D003497:Cyclic N-Oxides; D023581:HIV Fusion Inhibitors; D010091:Oximes; D010880:Piperidines; D011725:Pyridines; D000644:Quaternary Ammonium Compounds; D019713:Receptors, CCR5; C438583:Ancriviroc; C119369:TAK 779