CRYSTAL-STRUCTURES OF HIV-2 PROTEASE IN COMPLEX WITH INHIBITORS CONTAINING THE HYDROXYETHYLAMINE DIPEPTIDE ISOSTERE

Background: The HIV protease is essential for the life cycle of the vi rus and is an important target for the development of therapeutic trea tments against AIDS. The structures of HIV protease in complex with di fferent inhibitors have helped in understanding the interactions betwe en inhibitors and the protease and in the design and optimization of H IV protease inhibitors. Results: We report here crystal structures at up to 1.7 Angstrom resolution of the homodimeric HIV-2 protease in com plex with seven inhibitors containing the hydroxyethylamine dipeptide isostere. A novel dimethylphenoxyacetyl group that is present in some of these inhibitors is inserted between residues 48' and 49' in the fl ap of the protease and residues 29' and 30' (where a prime indicates a residue in the second monomer), which undergo a conformational change to accommodate the phenyl ring of the inhibitor. Conclusions: This st udy shows that besides the residues in the nap and residues 79-81 in t he S-1 substrate-binding pocket which undergo conformational changes u pon inhibitor binding, residues 29 and 30 can also adapt their conform ation to fit certain inhibitors. Conformational flexibility of the HIV protease plays an important role in inhibitor binding.