title: Characterization of a novel human immunodeficiency virus type 1 protease inhibitor, A-790742.
abstract: A-790742 is a potent human immunodeficiency virus type 1 (HIV-1) protease inhibitor, with 50% effective concentrations ranging from 2 to 7 nM against wild-type HIV-1. The activity of this compound is lowered by approximately sevenfold in the presence of 50% human serum. A-790742 maintained potent antiviral activity against lopinavir-resistant variants generated in vitro as well as against a panel of molecular clones containing proteases derived from HIV-1 patient isolates with multiple protease mutations. During in vitro selection, A-790742 selected two primary mutations (V82L and I84V) along with L23I, L33F, K45I, A71V/A, and V77I in the pNL4-3 background and two other mutations (A71V and V82G) accompanied by M46I and L63P in the HIV-1 RF background. HIV-1 pNL4-3 clones with a single V82L or I84V mutation were phenotypically resistant to A-790742 and ritonavir. Taking these results together, A-790742 displays a favorable anti-HIV-1 profile against both the wild type and a large number of mutants resistant to other protease inhibitors. The selection of the uncommon V82L and V82G mutations in protease by A-790742 suggests the potential for an advantageous resistance profile with this protease inhibitor.
authors.affiliation: Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois 60064, USA. tanya.chernyavskiy@abbott.com
authors.forename: Tatyana
authors.initials: T
authors.lastname: Dekhtyar
authors.forename: Teresa I
authors.initials: TI
authors.lastname: Ng
authors.forename: Liangjun
authors.initials: L
authors.lastname: Lu
authors.forename: Sherie
authors.initials: S
authors.lastname: Masse
authors.forename: David A
authors.initials: DA
authors.lastname: DeGoey
authors.forename: William J
authors.initials: WJ
authors.lastname: Flosi
authors.forename: David J
authors.initials: DJ
authors.lastname: Grampovnik
authors.forename: Larry L
authors.initials: LL
authors.lastname: Klein
authors.forename: Dale J
authors.initials: DJ
authors.lastname: Kempf
authors.forename: Akhteruzzaman
authors.initials: A
authors.lastname: Molla
mesh_terms: D024882:Drug Resistance, Viral / Q000235:genetics; D016333:HIV Protease / Q000187:drug effects / Q000235:genetics; D017320:HIV Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D061466:Lopinavir; D008826:Microbial Sensitivity Tests; D009154:Mutation; D010641:Phenotype; D011744:Pyrimidinones / Q000494:pharmacology; D012641:Selection, Genetic; D012692:Serial Passage
chemical_list: D017320:HIV Protease Inhibitors; D011744:Pyrimidinones; D061466:Lopinavir; D016333:HIV Protease