From nonpeptide toward noncarbon protease inhibitors

Metallacarboranes as specific and potent inhibitors of HIV protease

Petr Cígler, Milan Kožíšek, Pavlína Řezáčová, Jíří Brynda, Zbyszek Otwinowski, Jana Pokorná, Jaromír Plešek, Bohumír Grüner, Lucie Dolečková-Marešová, Martin Máša, Juraj Sedláček, Jochen Bodem, Hans Georg Kräusslich, Vladimír Král, Jan Konvalinka

Research output: Contribution to journalArticle

204 Citations (Scopus)

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 Pl 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 Ki value of 2.2 nM and a submicromolar EC50 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 Å 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.

Original languageEnglish (US)
Pages (from-to)15394-15399
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume102
Issue number43
DOIs
StatePublished - Oct 25 2005

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HIV Protease
HIV Protease Inhibitors
Protease Inhibitors
Cobalt
Antiviral Agents
Peptide Hydrolases
Sodium Compounds
Cathepsin D
Crystallography
Boron
Papain
Pepsin A
Drug Design
Amylases
Trypsin
Biological Availability
Hydrogen
Proteins
Costs and Cost Analysis
Enzymes

Keywords

  • Aspartic proteases
  • Carboranes
  • Rational drug design
  • Virostatics
  • X-ray structure analysis

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

From nonpeptide toward noncarbon protease inhibitors : Metallacarboranes as specific and potent inhibitors of HIV protease. / Cígler, Petr; Kožíšek, Milan; Řezáčová, Pavlína; Brynda, Jíří; Otwinowski, Zbyszek; Pokorná, Jana; Plešek, Jaromír; Grüner, Bohumír; Dolečková-Marešová, Lucie; Máša, Martin; Sedláček, Juraj; Bodem, Jochen; Kräusslich, Hans Georg; Král, Vladimír; Konvalinka, Jan.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 102, No. 43, 25.10.2005, p. 15394-15399.

Research output: Contribution to journalArticle

Cígler, P, Kožíšek, M, Řezáčová, P, Brynda, J, Otwinowski, Z, Pokorná, J, Plešek, J, Grüner, B, Dolečková-Marešová, L, Máša, M, Sedláček, J, Bodem, J, Kräusslich, HG, Král, V & Konvalinka, J 2005, 'From nonpeptide toward noncarbon protease inhibitors: Metallacarboranes as specific and potent inhibitors of HIV protease', Proceedings of the National Academy of Sciences of the United States of America, vol. 102, no. 43, pp. 15394-15399. https://doi.org/10.1073/pnas.0507577102
Cígler, Petr ; Kožíšek, Milan ; Řezáčová, Pavlína ; Brynda, Jíří ; Otwinowski, Zbyszek ; Pokorná, Jana ; Plešek, Jaromír ; Grüner, Bohumír ; Dolečková-Marešová, Lucie ; Máša, Martin ; Sedláček, Juraj ; Bodem, Jochen ; Kräusslich, Hans Georg ; Král, Vladimír ; Konvalinka, Jan. / From nonpeptide toward noncarbon protease inhibitors : Metallacarboranes as specific and potent inhibitors of HIV protease. In: Proceedings of the National Academy of Sciences of the United States of America. 2005 ; Vol. 102, No. 43. pp. 15394-15399.
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AU - Brynda, Jíří

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