Inorganic polyhedral metallacarborane inhibitors of HIV protease: a new approach to overcoming antiviral resistance.
HIV protease (PR) is a prime target for rational anti-HIV drug design. We have previously identified icosahedral metallacarboranes as a novel class of nonpeptidic protease inhibitors. Now we show that substituted metallacarboranes are potent and specific competitive inhibitors of drug-resistant HIV PRs prepared either by site-directed mutagenesis or cloned from HIV-positive patients. Molecular modeling explains the inhibition profile of metallacarboranes by their unconventional binding mode.
Kozísek
Milan
M
Gilead Sciences and IOCB Research Center Prague, Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Praha, Czech Republic.
Cígler
Petr
P
Lepsík
Martin
M
Fanfrlík
Jindrich
J
Rezácová
Pavlína
P
Brynda
Jirí
J
Pokorná
Jana
J
Plesek
Jaromír
J
Grüner
Bohumír
B
Grantz Sasková
Klára
K
Václavíková
Jana
J
Král
Vladimír
V
Konvalinka
Jan
J
D001896:Boron Compounds / Q000737:chemistry* / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D024882:Drug Resistance, Viral / Q000187:drug effects*; D016333:HIV Protease / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017320:HIV Protease Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology; D008670:Metals / Q000737:chemistry*; D008958:Models, Molecular; D015394:Molecular Structure; D009154:Mutation / Q000235:genetics
D001896:Boron Compounds; D017320:HIV Protease Inhibitors; D008670:Metals; D016333:HIV Protease