title: Inhibition of human immunodeficiency virus type 1 (HIV-1) replication by the dipyridodiazepinone BI-RG-587.
abstract: The dipyridodiazepinone human immunodeficiency virus type 1 (HIV-1)-specific reverse transcriptase (RT) inhibitor BI-RG-587 was tested for its ability to inhibit HIV-1 replication in both acutely and chronically infected cell lines. The ability of BI-RG-587 to inhibit steps in the virus replicative cycle other than reverse transcription was also assessed. BI-RG-587 was found to be a potent inhibitor of HIV-1 replication in acutely infected cells (50% inhibitory concentration [IC50] = 37.2 nM), and the sensitivity and kinetics of that inhibition was similar to the known RT inhibitor zidovudine (AZT). Even at 100x IC50, BI-RG-587 had no effect on gp120/CD4 interaction, syncytia formation, or envelope glycoprotein processing. In addition, no inhibition of viral replication or protein production was noted in a chronically infected cell line that produces viral products in an RT-independent manner. Finally, no inhibition of acute HIV-2 replication was noted, even with very high (2500x IC50 for HIV-1) concentrations of BI-RG-587. These results demonstrate that BI-RG-587 is a potent inhibitor of HIV-1 replication and that this inhibition occurs at the point of reverse transcription.
authors.affiliation: Department of Pediatrics, University of Massachusetts Medical School, Worcester 01605.
authors.forename: R A
authors.initials: RA
authors.lastname: Koup
authors.forename: V J
authors.initials: VJ
authors.lastname: Merluzzi
authors.forename: K D
authors.initials: KD
authors.lastname: Hargrave
authors.forename: J
authors.initials: J
authors.lastname: Adams
authors.forename: K
authors.initials: K
authors.lastname: Grozinger
authors.forename: R J
authors.initials: RJ
authors.lastname: Eckner
authors.forename: J L
authors.initials: JL
authors.lastname: Sullivan
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology*; D002460:Cell Line; D002461:Cell Line, Transformed; D015726:Giant Cells / Q000187:drug effects; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology / Q000502:physiology; D015498:HIV-2 / Q000187:drug effects; D006801:Humans; D019829:Nevirapine; D011725:Pyridines / Q000494:pharmacology*; D012191:Retroviridae Proteins / Q000096:biosynthesis / Q000187:drug effects; D018894:Reverse Transcriptase Inhibitors; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D011725:Pyridines; D012191:Retroviridae Proteins; D018894:Reverse Transcriptase Inhibitors; D019829:Nevirapine