5 Inhibitors of HIV Proteinase

Abstract

Publisher Summary This chapter focuses on inhibitors of HIV Proteinase. X-ray crystallographic structures of HIV proteinase complexed with a diverse range of inhibitors have now been published. Despite large differences in the structures of the bound inhibitors, the structure of the enzyme is remarkably well conserved in all of the complexes. The body of the proteinase is similar, in each case, to that of the native enzyme but the two flap regions are seen to have closed in on the bound inhibitor. The hydroxyl group of the inhibitors, where present, is situated between the carboxyl groups of the two catalytic aspartate residues and forms at least one hydrogen bond with each carboxylate. The majority of HIV proteinase-inhibitor complexes that have been examined show a tightly bound water molecule, which is buried deep within the active site. HIV-1 proteinase has been shown to be responsible for specific cleavage at nine distinct sites in the viral gag and gag-pol proteins. Successful approaches to the identification of inhibitors of HIV proteinase include random screening, the incorporation of transition-state mimetics into suitable peptide sequences and computer-assisted molecular modeling techniques.