A naphthyridine carboxamide provides evidence for discordant resistance between mechanistically identical inhibitors of HIV-1 integrase
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- 26 July 2004
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences
- Vol. 101 (31) , 11233-11238
- https://doi.org/10.1073/pnas.0402357101
Abstract
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.Keywords
This publication has 29 references indexed in Scilit:
- Discovery of a Novel Binding Trench in HIV IntegraseJournal of Medicinal Chemistry, 2004
- Development of Resistance against Diketo Derivatives of Human Immunodeficiency Virus Type 1 by Progressive Accumulation of Integrase MutationsJournal of Virology, 2003
- Design and Synthesis of 8-Hydroxy-[1,6]Naphthyridines as Novel Inhibitors of HIV-1 Integrase in Vitro and in Infected CellsJournal of Medicinal Chemistry, 2003
- Inhibition of HIV-1 Ribonuclease H by a Novel Diketo Acid, 4-[5-(Benzoylamino)thien-2-yl]-2,4-dioxobutanoic AcidJournal of Biological Chemistry, 2003
- HIV chemotherapyNature, 2001
- Crystal structures of the catalytic domain of HIV-1 integrase free and complexed with its metal cofactor: high level of similarity of the active site with other viral integrases 1 1Edited by R. HuberJournal of Molecular Biology, 1998
- Merck molecular force field. V. Extension of MMFF94 using experimental data, additional computational data, and empirical rulesJournal of Computational Chemistry, 1996
- Merck molecular force field. III. Molecular geometries and vibrational frequencies for MMFF94Journal of Computational Chemistry, 1996
- Merck molecular force field. II. MMFF94 van der Waals and electrostatic parameters for intermolecular interactionsJournal of Computational Chemistry, 1996
- Merck molecular force field. I. Basis, form, scope, parameterization, and performance of MMFF94Journal of Computational Chemistry, 1996