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S2 Inhibitors of HIV Integrase: Antiviral Activity and Mechanism. D. J. HAZUDA. Merck Res. Labs, West Point, PA.
The HIV-1 enzyme integrase represents a potential target for the development of selective anti-retroviral agents. We have identified novel inhibitors of integrase which exhibit antiviral activity specifically as a consequence of their effect on integration. These studies define a novel approach for discovering new antiretroviral agents.
Integration is a complex, multi-step process consisting of 1) assembly of a stable complex between the enzyme and specific viral DNA sequences, 2) endonucleolytic processing of the 3' end of the viral DNA, and 3) strand transfer of the 3' viral end into the host cell DNA. By uncoupling the reaction, we observed that integrase inhibitors can be segregated into two distinct classes, 1) compounds which prevent assembly and, 2) compounds which inhibit strand transfer. Inhibitors of assembly interact with the unliganded enzyme and have no effect on subsequent catalysis. These compounds do not inhibit in vitro integration catalyzed by pre-integration complexes isolated from HIV-1 infected cells and have little or no antiviral activity. In contrast, inhibitors of integrase which have antiviral activity are inhibitors of integrase catalyzed strand transfer. These compounds bind with high affinity only subsequent to assembly on the viral DNA, suggesting recognition by a specific conformational state of the active enzyme complex. Strand transfer inhibitors inhibit pre-integration complexes in vitro and inhibit integration and HIV-1 replication. We believe that the unique mechanism of action of these compounds accounts for their distinctive antiviral effect.
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