Identification of broad-based HIV-1 protease inhibitors from combinatorial libraries.
Clinically approved inhibitors of the HIV-1 protease function via a competitive mechanism. A particular vulnerability of competitive inhibitors is their sensitivity to increases in substrate concentration, as may occur during virion assembly, budding and processing into a mature infectious viral particle. Advances in chemical synthesis have led to the development of new high-diversity chemical libraries using rapid in-solution syntheses. These libraries have been shown previously to be effective at disrupting protein-protein and protein-nucleic acid interfaces. We have screened 44000 compounds from such a library to identify inhibitors of the HIV-1 protease. One compound was identified that inhibits wild-type protease, as well as a drug-resistant protease with six mutations. Moreover, analysis of this compound suggests an allosteric non-competitive mechanism of inhibition and may represent a starting point for an additional strategy for anti-retroviral therapy.
Chang
Max W
MW
Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA.
Giffin
Michael J
MJ
Muller
Rolf
R
Savage
Jeremiah
J
Lin
Ying C
YC
Hong
Sukwon
S
Jin
Wei
W
Whitby
Landon R
LR
Elder
John H
JH
Boger
Dale L
DL
Torbett
Bruce E
BE
D020650:Combinatorial Chemistry Techniques; D016333:HIV Protease / Q000187:drug effects; D017320:HIV Protease Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D021241:Spectrometry, Mass, Electrospray Ionization
D017320:HIV Protease Inhibitors; D016333:HIV Protease; C514803:p16 protease, Human immunodeficiency virus 1