The increasing incidence of resistance to current HIV-1 therapy underscores the need to develop antiretroviral agents with new mechanisms of action. Integrase, one of three viral enzymes essential for HIV-1 replication, presents an important yet unexploited opportunity for drug development. We describe here the identification and characterization of L-870,810, a small-molecule inhibitor of HIV-1 integrase with potent antiviral activity in cell culture and good pharmacokinetic properties. L-870,810 is an inhibitor with an 8-hydroxy-(1,6)-naphthyridine-7-carboxamide pharmacophore. The compound inhibits HIV-1 integrase-mediated strand transfer, and its antiviral activity in vitro is a direct consequence of this ascribed effect on integration. L-870,810 is mechanistically identical to previously described inhibitors from the diketo acid series; however, viruses selected for resistance to L-870,810 contain mutations (integrase residues 72, 121, and 125) that uniquely confer resistance to the naphthyridine. Conversely, mutations associated with resistance to the diketo acid do not engender naphthyridine resistance. Importantly, the mutations associated with resistance to each of these inhibitors map to distinct regions within the integrase active site. Therefore, we propose a model of the two inhibitors that is consistent with this observation and suggests specific interactions with discrete binding sites for each ligand. These studies provide a structural basis and rationale for developing integrase inhibitors with the potential for unique and nonoverlapping resistance profiles.A gents for the treatment of HIV-1 infection target two of the three virally encoded enzymes and belong to three mechanistic classes known as nucleoside reverse transcriptase, nonnucleoside reverse transcriptase (NNRTI), and protease inhibitors. Although treatment regimens comprising combinations of these agents have significantly reduced AIDS-related morbidity and mortality, it is estimated that 78% of treatment-naive patients harbor viruses that have evolved resistance to at least one of these drug classes (1, 2). The emergence of HIV-1 strains resistant to reverse transcriptase and protease inhibitors highlights the need to develop antiviral agents with novel mechanisms of action.Integrase (3, 4), one of the three virally encoded enzymes required for HIV-1 replication, catalyses the integration of viral DNA into the genome of the host cell. The integration reaction requires three discrete steps: assembly of a stable preintegration complex at the termini of the viral DNA and two sequential transesterification reactions. In the first reaction, 3Ј-end processing, endonucleolytic cleavage of the two 3Ј nucleotides at each DNA end generates 3Ј-hydroxyl groups that function as nucleophiles in the second reaction. The strand breakage of the cellular DNA and concomitant covalent linkage to the viral DNA is a consequence of the second transesterification reaction, strand transfer.The discovery of a series of diketo acids containing HIV-1 integrase i...
