NDLI: A naphthyridine carboxamide provides evidence for discordant resistance between mechanistically identical inhibitors of HIV-1 integrase

Content Provider	PubMed Central
Author	Hazuda, Daria J. Anthony, Neville J. Gomez, Robert P. Jolly, Samson M. Wai, John S. Zhuang, Linghang Fisher, Thorsten E. Embrey, Mark Guare, James P. Egbertson, Melissa S. Vacca, Joseph P. Huff, Joel R. Felock, Peter J. Witmer, Marc V. Stillmock, Kara A. Robert, Danovich Grobler, Jay Miller, Michael D. Espeseth, Amy S. Jin, Lixia Chen, I-wu Lin, Jiunn H. Kassahun, Kelem Ellis, Joan D. Wong, Bradley K. Xu, Wei Pearson, Paul G. Schleif, William A. Cortese, Riccardo Emini, Emilio Summa, Vincenzo Holloway, M. Katharine Young, Steven D.
Copyright Year	2004
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.
Related Links	http://dx.doi.org/10.1073/pnas.0402357101
Ending Page	11238
Page Count	6
Starting Page	11233
File Format	PDF
ISSN	00278424
e-ISSN	10916490
Journal	Proceedings of the National Academy of Sciences of the United States of America
Issue Number	31
Volume Number	101
Language	English
Publisher	National Academy of Sciences
Publisher Date	2004-08-03
Access Restriction	Open
Rights Holder	National Academy of Sciences
Subject Keyword	General Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Multidisciplinary

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3	National Digital Library of India Office, Indian Institute of Technology Kharagpur	The administrative and infrastructural headquarters of the project	Dr. B. Sutradhar bsutra@ndl.gov.in
4	Project PI / Joint PI	Principal Investigator and Joint Principal Investigators of the project	Dr. B. Sutradhar bsutra@ndl.gov.in Prof. Saswat Chakrabarti will be added soon
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