Author(s): Poppe, Susan M*, Slade D*, Chong K*, Hinshaw R*, Pagano P*, Markowitz M**, Ho D**, Mo H**, Gorman R***, Tarpley W*. *Pharmacia & Upjohn, Kalamazoo, MI, USA; **Aaron Diamond AIDS Research Center, New York University School of Medicine, New York, NY, USA; ***Wayne State University School of Medicine, Detroit, MI, USA
Abstract:
Objective: To fully characterize the antiviral activities of the dihydropyrone non-peptidic HIV protease inhibitors especially with regard to their potency versus HIV-1 isolates highly resistant to peptidemimetic inhibitors (e.g., ritonavir, indinavir, saquinivir, nelfinavir). Methods: Antiviral assays utilized multiple viral isolates and cell types. Viral replication was quantitated by measuring p24 by ELISA. Inhibitory concentrations at 50 and 90 percent (IC50, IC90) were derived by linear regression analysis of dose-response curves.
Results: The lead dihydropyrone inhibitors potently block replication of multiple isolates of HIV (IC90s ~200 nM). NL4-3 variants [Mo et al., Abstract, ASM Conference, 1995] 10-100 fold resistant to ritonavir, indinavir, saquinivir, and nelfinavir remained sensitive to low concentrations of dihydropyrone inhibitors; the dihydropyrone IC90s were increased only 3-10 fold. Consistent with these data, clinical HIV isolates broadly resistant to peptidic inhibitors are also potently blocked by the dihydropyrones (IC90 =A31 =B5M). Efforts to derive dihydropyrone-resistant HIV-1 are in progress; after six months of continuous exposure of virus to escalating drug concentrations, highly-resistant virus has not been obtained.
Conclusions: The dihydropyrone inhibitors are potent anti-HIV agents with antiviral activity similar to the peptidemimetic inhibitors. These data also suggest the resistance pattern for the dihydropyrones are distinct from the peptidemimetic inhibitors.
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