COMPARATIVE-ANALYSIS OF THE X-RAY STRUCTURES OF HIV-1 AND HIV-2 PROTEASES IN COMPLEX WITH CGP-53820, A NOVEL PSEUDOSYMMETRIC INHIBITOR

Background: The human immunodeficiency virus (HIV) is the causative ag ent of acquired immunodeficiency syndrome (AIDS). Two subtypes of the virus, HIV-1 and HIV-2, have been characterized The protease enzymes f rom these two subtypes, which are aspartic acid proteases and have bee n found to be essential for maturation of the infectious particle, sha re about 50% sequence identity. Differences in substrate and inhibitor binding between these enzymes have been previously reported. Results: We report the X-ray crystal structures of both HIV-1 and HIV-2 protea ses each in complex with thepseudosymmetric inhibitor, CGP 53820, to 2 .2 Angstrom and 2.3 Angstrom, respectively. In both structures, the en tire enzyme and inhibitor could be located. The structures confirmed e arlier modeling studies. Differences between the CGP 53820 inhibitory binding constants for the two enzymes could be correlated with structu ral differences. Conclusions: Minor sequence changes in subsites at th e active site can explain some of the observed differences in substrat e and inhibitor binding between the two enzymes. The information gaine d from this investigation may help in the design of equipotent HIV-1/H IV-2 protease inhibitors.