3rd International Workshop on HIV Drug Resistance & Treatment Strategies 23-26 June 1999, San Diego, California, USA

INHIBITORS OF HIV INTEGRASE: ANTIVIRAL ACTIVITY AND MECHANISM

Antiviral Therapy 1999;4 (Suppl 1):3 (abstract no. 1)

DJ Hazuda
Merck Research Laboratories, West Point, Pennsylvania, USA

The HIV-1 enzyme integrase represents a potential target for the development of selective antiretroviral agents. We have identified novel inhibitors of integrase that block integration and inhibit HIV-1 replication in cells. The isolation and characterization of resistant viral isolates has established integrase as the specific target of inhibition thus validating integrase as a viable target for chemotherapeutic intervention. These inhibitors of integrase that have antiviral activity are inhibitors of integrase-catalysed strand transfer and are structurally and mechanistically distinct from previously described inhibitors of the enzyme. Integration is a complex, multi-step process consisting of: (i) assembly of a stable complex between the enzyme and specific viral DNA. sequences; (ii) endonucleolytic processing of the 3' end of the viral DNA; and (iii) 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: (i) compounds that prevent assembly; and (ii) compounds that 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 catalysed by pre-integration complexes isolated from HIV-1-infected cells and have little or no antiviral activity. In general, known inhibitors of integrase fall into this class. In contrast, inhibitors of strand transfer bind with high affinity only subsequent to assembly on the viral DNA, suggesting recognition by a specific conformational state of the bound enzyme. Strand transfer inhibitors inhibit pre-integration complexes in vitro and inhibit integration and HIV-1 replication. We believe that the unique mechanism of action exhibited by these novel compounds accounts for their distinctive antiviral activity and their ability to effectively block integration in HIV-1-infected cells.

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