15th International HIV Drug Resistance Workshop 13-17 June 2006, Sitges, Spain

METALLACARBORANES AS SPECIFIC AND POTENT INHIBITORS OF HIV PROTEASE AND ITS RESISTANT MUTANTS

Antivir Ther. 2006, 11:S29 (abstract no. 24)

J Pokorná¹, P Cígler¹, M Kozísek¹, P Rezácová², J Brynda², J Plesek³, B Grüner³, J Sedlácek², J Bodem⁴, H-G Kraeusslich⁴, V Král⁵ and J Konvalinka^1
1Institute of Organic Chemistry and Biochemistry, Academy of Science of the Czech Republic, Prague; ²Institute of Molecular Genetics, Academy of Science of the Czech Republic, Prague; ³Institute of Inorganic Chemistry, Academy of Science of the Czech Republic; ⁴Department of Virology, University of Heidelberg, Germany; ⁵Department of Analytical Chemistry, Institute of Chemical Technology, Prague, Czech Republic

BACKGROUND: HIV protease (PR) represents a prime target for rational drug design and protease inhibitors (PIs) are powerful antiviral drugs. In our search for novel PI structures, we identified group of inorganic compounds, icosahedral carboranes, as candidates for a novel class of non-peptidic PIs.

METHODS: The synthesis started from easily accessible parent cobalt bis(dicarbollide) ion to yield either 8-hydroxyderivative or the 8-dioxane-3-cobalt bis(1,2-dicarbollide) reagent that was subsequently reacted under mild conditions giving rise to a series of exo-skeletally modified metallacarborane cluster anions. These compounds were tested for their ability to inhibit panel of recombinant resistant HIV PRs prepared either by site-directed mutagenesis or cloned from HIV-positive patients treated by HAART for a prolonged period of time. The activity of selected compounds was also determined in tissue culture. The structure of Metallacarborane-protease complex was determined by X-ray crystallography and refined to 2.15 Å resolution.

RESULTS: Substituted metallacarboranes are potent, specific and selective competitive inhibitors of the wild-type and mutated HIV PRs. The most active compound exhibited a K_i value of 2.2 nM and a submicromolar EC₅₀ in antiviral tests and showed no toxicity in tissue culture. The structure of the parent compound in complex with HIV PR was determined at 2.15 Å resolution by X-ray crystallography (Cígler et al., Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15394-9). The inhibitors show novel binding mode to the PR binding pockets and are potent inhibitors of a panel of resistant PR species, harbouring mutations responsible for the resistant phenotype.

CONCLUSIONS: The novel type of binding, chemical and biological stability, low toxicity and the possibility to introduce various modifications make boron clusters attractive novel pharmacophores for potent and specific inhibition of drug-resistant HIV species.

2006-06-13
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