The HIV protease represents a crucial virus-specific target for new therapies of AIDS. Such an approach is one way of inhibiting the production of mature, infectious virions in chronically HIV-infected cells. Recently, a number of antiretroviral peptide analogs have been synthesized based on the knowledge of physiology and structure of HIV-1 protease. One class of such protease inhibitors is C2 symmetric protease inhibitor. Logical extension of current approaches for therapy of HIV infection would be the use of combinations of multiple antiviral agents which have different antiretroviral mechanism(s). Thus, we have explored whether symmetric HIV protease inhibitors are active against a variety of HIV strains and synergize with dideoxynucleosides such as AZT or ddl in vitro. We have also asked whether such inhibitors cause irreversible changes to HIV protease. In the present report, we describe that C2 symmetric HIV protease inhibitors tested in this study had a potent antiviral activity against a wide range of HIV isolates including monocytotropic strains and primary HIV-1 isolates. We also demonstrate and discuss the effects of combinations of C2 symmetric HIV protease inhibitors and AZT or ddI, dideoxynucleoside analogues which are already in a clinical domain.
