title: From nonpeptide toward noncarbon protease inhibitors: metallacarboranes as specific and potent inhibitors of HIV protease.
abstract: HIV protease (PR) represents a prime target for rational drug design, and protease inhibitors (PI) are powerful antiviral drugs. Most of the current PIs are pseudopeptide compounds with limited bioavailability and stability, and their use is compromised by high costs, side effects, and development of resistant strains. In our search for novel PI structures, we have identified a group of inorganic compounds, icosahedral metallacarboranes, as candidates for a novel class of nonpeptidic PIs. Here, we report the potent, specific, and selective competitive inhibition of HIV PR by substituted metallacarboranes. The most active compound, sodium hydrogen butylimino bis-8,8-[5-(3-oxa-pentoxy)-3-cobalt bis(1,2-dicarbollide)]di-ate, exhibited a K(i) value of 2.2 nM and a submicromolar EC(50) in antiviral tests, showed no toxicity in tissue culture, weakly inhibited human cathepsin D and pepsin, and was inactive against trypsin, papain, and amylase. The structure of the parent cobalt bis(1,2-dicarbollide) in complex with HIV PR was determined at 2.15 A resolution by protein crystallography and represents the first carborane-protein complex structure determined. It shows the following mode of PR inhibition: two molecules of the parent compound bind to the hydrophobic pockets in the flap-proximal region of the S3 and S3' subsites of PR. We suggest, therefore, that these compounds block flap closure in addition to filling the corresponding binding pockets as conventional PIs. This type of binding and inhibition, chemical and biological stability, low toxicity, and the possibility to introduce various modifications make boron clusters attractive pharmacophores for potent and specific enzyme inhibition.
authors.affiliation: Institutes of Organic Chemistry and Biochemistry and Molecular Genetics, Academy of Sciences of the Czech Republic, Flemingovo námestí 2, 166 10 Prague 6, Czech Republic.
authors.forename: Petr
authors.initials: P
authors.lastname: Cígler
authors.forename: Milan
authors.initials: M
authors.lastname: Kozísek
authors.forename: Pavlína
authors.initials: P
authors.lastname: Rezácová
authors.forename: Jírí
authors.initials: J
authors.lastname: Brynda
authors.forename: Zbyszek
authors.initials: Z
authors.lastname: Otwinowski
authors.forename: Jana
authors.initials: J
authors.lastname: Pokorná
authors.forename: Jaromír
authors.initials: J
authors.lastname: Plesek
authors.forename: Bohumír
authors.initials: B
authors.lastname: Grüner
authors.forename: Lucie
authors.initials: L
authors.lastname: Dolecková-Maresová
authors.forename: Martin
authors.initials: M
authors.lastname: Mása
authors.forename: Juraj
authors.initials: J
authors.lastname: Sedlácek
authors.forename: Jochen
authors.initials: J
authors.lastname: Bodem
authors.forename: Hans-Georg
authors.initials: HG
authors.lastname: Kräusslich
authors.forename: Vladimír
authors.initials: V
authors.lastname: Král
authors.forename: Jan
authors.initials: J
authors.lastname: Konvalinka
mesh_terms: D016282:Aspartic Acid Endopeptidases / Q000737:chemistry; D001880:Boranes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D018360:Crystallography, X-Ray; D015195:Drug Design; D016333:HIV Protease / Q000737:chemistry; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D001880:Boranes; D017320:HIV Protease Inhibitors; D016282:Aspartic Acid Endopeptidases; D016333:HIV Protease; C065184:p16 protease, Human immunodeficiency virus 2