Biologically (Pharmaceutically) Active Boron Clusters


Synthesis and design of carborane based HIV Protease inhibitors

Contact person: B. Grüner

Scientists from the Institute of Inorganic Chemistry, Academy of Sciences of the Czech Republic play a key role in a broader interdisciplinary cooperation focused on design and development of biologically active carboranes and metallacarboranes. This joint research proceeds within mutual collaboration of several research teams from IOCHB AS ČR (Groups of J. Konvalinka and P. Řezáčová), IMG AS ČR (J. Brynda), Dpt. of Physical and polymer chemistry, Faculty of Natural Sciences of the Charles Univ. (P. Matějíček) and Institute of Analytical chemistry VŠCHT (Group of V. Král). The joint effort resulted in recent discovery of inorganic non-peptidomimetic inhibitors of HIV-1 protease enzyme (HIV-1-PR) exhibiting a novel and unique mechanism of their action. A high efficacy and specific inhibitory action for HIV-PR enzyme has been demonstrated for various carborane compounds, in particular for these based on highly hydrophobic cobalt bis(dicarbollide) ion.

These compounds exhibited also promisingly high activity towards several HIV PR isoforms isolated from resistant mutants of the HIV virus strains. In the figure on the right, there is an X-ray structure of HIV-PR enzyme with two incorporated cobalt bis(dizarbollide)1- ions (the synchrotron structure and refining: P. Řezácová, J. Brynda, Z. Otwinowski). More recently, we have initiated a search for effective carborane and metallacarborane inhibitors addressing several other selected viral and human enzymes, which form current important primary targets in the rational drug design. For more information on the metallacarborane HIV-PR inhibitors see the literature below.

Selected Papers

  • 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., Krausslich H. G., Král V., Konvalinka J. Proc. Natl. Acad. Sci. U. S. A. 102(43), 15394-15399, 2005.
  • M. Kožíšek, P. Cígler, M. Lepšík, J. Fanfrlík, P. Řezáčová, J. Brynda, J. Pokorná, J. Plešek, B. Grüner, K. Grantz-Šašková, J.Václavíková,  H.-G. Kraeusslich, V. Král, J. Konvalinka  Inorganic polyhedral metallacarborane inhibitors of HIV protease – a new approach to vercoming antiviral resistance  J. Med. Chem. 51(15), 4839-4843 (2008).
  • P. Řezáčová, J. Pokorná, J. Brynda, M. Kožíšek, P. Cígler, M. Lepšík, J. Fanfrlík, J. Řezáč, K. Grantz-Šašková, I. Sieglová, J. Plešek, V. Šícha, B. Grűner, H. Oberwinkler, J. Sedláček, H.-G. Kräusslich, P. Hobza, V. Král, J. Konvalinka, Design of Potent HIV Protease Inhibitors Based on Inorganic Polyhedral Metalla-carboranes. J. Med. Chem. 52, 7132-7141 (2009). 
  • P. Řezáčová, P. Cígler, P. Matějíček, M. Lepšík,  J. Pokorná,  B. Grüner and J. Konvalinka "Medicinal Application of Carboranes: Chapter 3, Medicinal Application of Carboranes: Inhibition of HIV Protease, in Boron Science- New Technologies and Applications, N.S. Hosmane, Editor., CRC Press: New York, ISBN-978-1-4398266-3-8.
  • Grüner B., Švec P. Hájková Z., Císařová I.,  Pokorná J.,  Konvalinka J., Derivatization chemistry of the double-decker dicobalt sandwich ion targeted to design biologically active substances, Pure Appl. Chem., 84(11), pp. 2243–2262, 2012.
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