Design and synthesis of HIV-1 protease inhibitors. Novel tetrahydrofuran P2/P2'-groups interacting with Asp29/30 of the HIV-1 protease. Determination of binding from X-ray crystal structure of inhibitor protease complex.
A series of HIV-1 protease inhibitors having new tetrahydrofuran P2/P2' groups have been synthesised and tested for protease inhibition and antiviral activity. Six novel 4-aminotetrahydrofuran derivatives were prepared starting from commercially available isopropylidene-alpha-D-xylofuranose yielding six symmetrical and six unsymmetrical inhibitors. Promising sub nanomolar HIV-1 protease inhibitory activities were obtained. The X-ray crystal structure of the most potent inhibitor (23, K(i) 0.25 nM) co-crystallised with HIV-1 protease is discussed and the binding compared with inhibitors 1a and 1b.
Oscarsson
Karin
K
Department of Organic Chemistry, Arrhenius Laboratory, Floor 6, Stockholm University, S-106 91 Stockholm, Sweden.
Lahmann
Martina
M
Lindberg
Jimmy
J
Kangasmetsä
Jussi
J
Unge
Torsten
T
Oscarson
Stefan
S
Hallberg
Anders
A
Samuelsson
Bertil
B
D018360:Crystallography, X-Ray; D015195:Drug Design; D005663:Furans / Q000737:chemistry*; D016333:HIV Protease / Q000737:chemistry* / Q000187:drug effects; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D015497:HIV-1 / Q000201:enzymology*; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008968:Molecular Conformation
D005663:Furans; D017320:HIV Protease Inhibitors; D007202:Indicators and Reagents; D016333:HIV Protease