HIV protease is responsible for the processing of viral polyproteins into mature structural proteins and enzymes that form new, infectious viral particle. Chemical inhibition or inactivation by mutation of PR blocks the infectivity of the virus. PR has thus become a prime target for therapeutic intervention in AIDS. Major research effort lead to the rapid development of eight effective inhibitors that are currently in clinical use, with several others still in the pipeline. In spite of the considerable success of rational drug design, the need for effective protease inhibitors (PIs) is still urgent. The clinical use of current Pis is compromised by high production cost, various side-effects and rapid development ofviral resistance. Therefore, there is a continuing need for the design of new PIs with an emphasis on broad specificity against PI-resistant HIV mutants.

Recently, we have reported the potent, specific and selective inhibition of HIV PR by parental and substituted metallacarboranes, namely cobalt bis(1,2-dicarbollides) (Cigler et al., 2005). We provided evidence for the mechanism of action of these compounds, show their antiviral activity in tissue cultures, analyze their binding towards the enzyme by X-ray crystallography and show the potential of this class of compounds to become a novel pharmacophore for enzyme inhibition.

Selected papers:

• Weber et al. (2002). Unusual binding mode of an HIV-1 protease inhibitor explains its potency against multi-drug-resistant virus strains. J. Mol. Biol.324, 739-754.
  
  
• Prejdová et al. (2004). Determining and Overcoming Resistance to HIV Protease Inhibitors. Current Drug Targets -Infect. Disord.4, 137-152.