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.
Seibert
Christoph
C
Laboratory of Molecular Biology and Biochemistry, The Rockefeller University, New York, NY 10021, USA. seiberc@mail.rockefeller.edu
Ying
Weiwen
W
Gavrilov
Svetlana
S
Tsamis
Fotini
F
Kuhmann
Shawn E
SE
Palani
Anandan
A
Tagat
Jayaram R
JR
Clader
John W
JW
McCombie
Stuart W
SW
Baroudy
Bahige M
BM
Smith
Steven O
SO
Dragic
Tatjana
T
Moore
John P
JP
Sakmar
Thomas P
TP
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