title: In vitro antiviral activity of the novel, tyrosyl-based human immunodeficiency virus (HIV) type 1 protease inhibitor brecanavir (GW640385) in combination with other antiretrovirals and against a panel of protease inhibitor-resistant HIV.
abstract: Brecanavir, a novel tyrosyl-based arylsulfonamide, high-affinity, human immunodeficiency virus type 1 (HIV-1) protease inhibitor (PI), has been evaluated for anti-HIV activity in several in vitro assays. Preclinical assessment of brecanavir indicated that this compound potently inhibited HIV-1 in cell culture assays with 50% effective concentrations (EC(50)s) of 0.2 to 0.53 nM and was equally active against HIV strains utilizing either the CXCR4 or CCR5 coreceptor, as was found with other PIs. The presence of up to 40% human serum decreased the anti-HIV-1 activity of brecanavir by 5.2-fold, but under these conditions the compound retained single-digit nanomolar EC(50)s. When brecanavir was tested in combination with nucleoside reverse transcriptase inhibitors, the antiviral activity of brecanavir was synergistic with the effects of stavudine and additive to the effects of zidovudine, tenofovir, dideoxycytidine, didanosine, adefovir, abacavir, lamivudine, and emtricitabine. Brecanavir was synergistic with the nonnucleoside reverse transcriptase inhibitor nevirapine or delavirdine and was additive to the effects of efavirenz. In combination with other PIs, brecanavir was additive to the activities of indinavir, lopinavir, nelfinavir, ritonavir, amprenavir, saquinavir, and atazanavir. Clinical HIV isolates from PI-experienced patients were evaluated for sensitivity to brecanavir and other PIs in a recombinant virus assay. Brecanavir had a <5-fold increase in EC(50)s against 80% of patient isolates tested and had a greater mean in vitro potency than amprenavir, indinavir, lopinavir, atazanavir, tipranavir, and darunavir. Brecanavir is by a substantial margin the most potent and broadly active antiviral agent among the PIs tested in vitro.
authors.affiliation: Department of Virology, GlaxoSmithKline, 5 Moore Dr., P.O. Box 13398, Research Triangle Park, NC 27709, USA. richard.j.hazen@gsk.com
authors.forename: Richard
authors.initials: R
authors.lastname: Hazen
authors.forename: Robert
authors.initials: R
authors.lastname: Harvey
authors.forename: Robert
authors.initials: R
authors.lastname: Ferris
authors.forename: Charles
authors.initials: C
authors.lastname: Craig
authors.forename: Phillip
authors.initials: P
authors.lastname: Yates
authors.forename: Philip
authors.initials: P
authors.lastname: Griffin
authors.forename: John
authors.initials: J
authors.lastname: Miller
authors.forename: Istvan
authors.initials: I
authors.lastname: Kaldor
authors.forename: John
authors.initials: J
authors.lastname: Ray
authors.forename: Vincente
authors.initials: V
authors.lastname: Samano
authors.forename: Eric
authors.initials: E
authors.lastname: Furfine
authors.forename: Andrew
authors.initials: A
authors.lastname: Spaltenstein
authors.forename: Michael
authors.initials: M
authors.lastname: Hale
authors.forename: Roger
authors.initials: R
authors.lastname: Tung
authors.forename: Marty
authors.initials: M
authors.lastname: St Clair
authors.forename: Mary
authors.initials: M
authors.lastname: Hanlon
authors.forename: Lawrence
authors.initials: L
authors.lastname: Boone
mesh_terms: D000465:Algorithms; D044966:Anti-Retroviral Agents / Q000494:pharmacology*; D052117:Benzodioxoles / Q000494:pharmacology*; D001798:Blood Proteins / Q000494:pharmacology; D002219:Carbamates / Q000494:pharmacology*; D002460:Cell Line; D024882:Drug Resistance, Viral / Q000187:drug effects*; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects*; D006367:HeLa Cells; D006801:Humans; D009961:Orosomucoid / Q000494:pharmacology; D010641:Phenotype; D044967:Serum / Q000737:chemistry; D012709:Serum Albumin / Q000494:pharmacology; D014443:Tyrosine / Q000737:chemistry*
chemical_list: D044966:Anti-Retroviral Agents; D052117:Benzodioxoles; D001798:Blood Proteins; D002219:Carbamates; D017320:HIV Protease Inhibitors; D009961:Orosomucoid; D012709:Serum Albumin; D014443:Tyrosine; C512121:brecanavir