Inhibitors of strand transfer that prevent integration and inhibit HIV-1 replication in cells.
Integrase is essential for human immunodeficiency virus-type 1 (HIV-1) replication; however, potent inhibition of the isolated enzyme in biochemical assays has not readily translated into antiviral activity in a manner consistent with inhibition of integration. In this report, we describe diketo acid inhibitors of HIV-1 integrase that manifest antiviral activity as a consequence of their effect on integration. The antiviral activity of these compounds is due exclusively to inhibition of one of the two catalytic functions of integrase, strand transfer.
Hazuda
D J
DJ
Department of Antiviral Research, Merck Research Laboratories, West Point, PA 19486, USA. daria-hazuda@merck.com
Felock
P
P
Witmer
M
M
Wolfe
A
A
Stillmock
K
K
Grobler
J A
JA
Espeseth
A
A
Gabryelski
L
L
Schleif
W
W
Blau
C
C
Miller
M D
MD
D000090:Acetoacetates / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D019380:Anti-HIV Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D002384:Catalysis / Q000187:drug effects; D018920:Coculture Techniques; D004270:DNA, Circular / Q000096:biosynthesis / Q000378:metabolism; D004279:DNA, Viral / Q000096:biosynthesis / Q000378:metabolism; D004352:Drug Resistance, Microbial; D019427:HIV Integrase / Q000235:genetics / Q000378:metabolism*; D019428:HIV Integrase Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D016325:HIV Long Terminal Repeat / Q000187:drug effects; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics / Q000502:physiology; D006801:Humans; D009154:Mutation; D011758:Pyrroles / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D013601:T-Lymphocytes / Q000821:virology; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D016662:Virus Integration / Q000187:drug effects*; D014779:Virus Replication / Q000187:drug effects
D000090:Acetoacetates; D019380:Anti-HIV Agents; D004270:DNA, Circular; D004279:DNA, Viral; D019428:HIV Integrase Inhibitors; C403887:L 708906; C403886:L 731988; D011758:Pyrroles; D011994:Recombinant Proteins; D019427:HIV Integrase