A naphthyridine carboxamide provides evidence for discordant resistance between mechanistically identical inhibitors of HIV-1 integrase.
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.
Department of Biological Chemistry, Merck Research Laboratories, P.O. Box 4, West Point, PA 19486, USA. daria_hazuda@merck.com
Daria J
DJ
Hazuda
Neville J
NJ
Anthony
Robert P
RP
Gomez
Samson M
SM
Jolly
John S
JS
Wai
Linghang
L
Zhuang
Thorsten E
TE
Fisher
Mark
M
Embrey
James P
JP
Guare
Melissa S
MS
Egbertson
Joseph P
JP
Vacca
Joel R
JR
Huff
Peter J
PJ
Felock
Marc V
MV
Witmer
Kara A
KA
Stillmock
Robert
R
Danovich
Jay
J
Grobler
Michael D
MD
Miller
Amy S
AS
Espeseth
Lixia
L
Jin
I-Wu
IW
Chen
Jiunn H
JH
Lin
Kelem
K
Kassahun
Joan D
JD
Ellis
Bradley K
BK
Wong
Wei
W
Xu
Paul G
PG
Pearson
William A
WA
Schleif
Riccardo
R
Cortese
Emilio
E
Emini
Vincenzo
V
Summa
M Katharine
MK
Holloway
Steven D
SD
Young
D000818:Animals; D002478:Cells, Cultured; D004285:Dogs; D018432:Drug Resistance, Multiple; D024882:Drug Resistance, Viral; D015658:HIV Infections / Q000188:drug therapy*; D019427:HIV Integrase / Q000235:genetics / Q000378:metabolism; D019428:HIV Integrase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D015498:HIV-2 / Q000187:drug effects; D006801:Humans; D008253:Macaca mulatta; D008297:Male; D016297:Mutagenesis, Site-Directed; D009287:Naphthyridines / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D015302:Simian Immunodeficiency Virus / Q000187:drug effects; D013601:T-Lymphocytes / Q000166:cytology / Q000821:virology; D016662:Virus Integration / Q000187:drug effects
D019428:HIV Integrase Inhibitors; C489415:L870810; D009287:Naphthyridines; D019427:HIV Integrase