ABSTRACT
The aspartic protease of the human immunode™ciency virus (HIV PR) is one of the most extensively studied enzymes known to man. More than 400 x-ray structures of the protein in the presence or absence of ligands or inhibitors have been determined to date, and the symmetric depictions of this dimeric enzyme have become one of the icons of modern structural biology. The HIV protease is crucial for the production of infectious viral particles (Kohl, 1988), and PR inhibitors (PIs) are potent and speci™c anti-HIV drugs. The successful rational design of HIV PIs is one of the most striking examples of structure-based drug design. In this chapter, we explain why the design of novel, potent PIs is still urgently needed and that derivatives of cobalt(III) bis(dicarbollide)(1-) ion [(1,2-C2B9H11)- 3,3′-Co(III)](1-), a compound well known to the carborane community (Hawthorne, 1965;
3.1 Introduction ............................................................................................................................ 41 3.2 Role of HIV Protease in the Viral Life Cycle ........................................................................ 42 3.3 Clinically Used HIV Protease Inhibitors ............................................................................... 43 3.4 From Pseudomimetics to Nonpeptidic HIV Protease Inhibitors ............................................ 45 3.5 Carborane Clusters as HIV PIs ...............................................................................................46 3.6 Structure-Activity Analysis of Selected Carboranes: Single-Cluster Compounds ...............46 3.7 Structure-Activity Analysis of Selected Metallacarborane: Double (Triple)-Cluster
Compounds ............................................................................................................................. 56 3.8 Antiviral Activity and Inhibition of Resistant HIV PR Species ............................................. 58 3.9 Structural Studies of HIV PR-Metallacarborane Binding...................................................... 59 3.10 Noncovalent Interactions of Heteroboranes with Biomolecules: Theoretical Considerations ..................................................................................................... 62 3.11 Aggregation of Metallacarboranes in Aqueous Media ...........................................................64 3.12 Summary ................................................................................................................................66 Acknowledgments ............................................................................................................................66 References ........................................................................................................................................66
