In vitro anti-HIV-1 activity of HIV protease inhibitor KNI-272 in resting and activated cells: implications for its combined use with AZT or ddI.

KNI-272, a conformationally constrained human immunodeficiency virus (HIV) protease inhibitor containing a P1 allophenylnorstatine (Apns) ((2S,3S)- 3-amino-2-hydroxy-4-phenylbutyric acid), has been shown to be a selective and potent inhibitor of the replication of a wide spectrum of HIV strains in vitro. When KNI-272 was tested in combination with 3'-azido-2',3'-dideoxythymidine (AZT) or 2',3'-dideoxyinosine (ddI) against a primary HIV-1 isolate in phytohemagglutin-activated peripheral blood mononuclear cells (PHA-PBM), its activity was identified to be additive, but not synergistic or antagonistic, as analyzed with the COMBO program package. When tested alone for anti-HIV-1 activity in resting PBM (R-PBM) and PHA-PBM, KNI-272 was found to be comparably potent against the virus in both target cell populations, whereas AZT was more potent in PHA-PBM than in R-PBM and ddI was more potent in R-PBM. These data suggest a potential clinical application of KNI-272 and its analogs.