title: Antiviral properties of palinavir, a potent inhibitor of the human immunodeficiency virus type 1 protease.
abstract: Palinavir is a potent inhibitor of the human immunodeficiency virus type 1 (HIV-1) and type 2 (HIV-2) proteases. Replication of laboratory strains (HIV-1, HIV-2, and simian immunodeficiency virus) and HIV-1 clinical isolates is inhibited by palinavir with 50% effective concentrations ranging from 0.5 to 30 nM. The average cytotoxic concentration of palinavir (35 microM) in the various target cells indicates a favorable therapeutic index. Potent antiviral activity is retained with increased doses of virus and with clinical isolates resistant to zidovudine (AZT), didanosine (ddI), or nevirapine. Combinations of palinavir with either AZT, ddI, or nevirapine demonstrate synergy or additivity in the inhibition of HIV-1 replication. Palinavir retains anti-HIV-1 activity when administered postinfection until times subsequent to the reverse transcription step. In chronically infected CR-10 cells, palinavir blocks Gag precursor polyprotein processing completely, reducing greater than 99% of infectious particle production. The results indicate that the antiviral activity of palinavir is specific to inhibition of the viral protease and occurs at a late stage in the replicative cycle of HIV-1. On the basis of the potent in vitro activity, low-level cytotoxicity, and other data, palinavir was selected for in-depth preclinical evaluation.
authors.affiliation: Department of Biochemistry, Bio-Méga Research Division of Boehringer Ingelheim (Canada) Ltd., Laval, Quebec.
authors.forename: D
authors.initials: D
authors.lastname: Lamarre
authors.forename: G
authors.initials: G
authors.lastname: Croteau
authors.forename: E
authors.initials: E
authors.lastname: Wardrop
authors.forename: L
authors.initials: L
authors.lastname: Bourgon
authors.forename: D
authors.initials: D
authors.lastname: Thibeault
authors.forename: C
authors.initials: C
authors.lastname: Clouette
authors.forename: M
authors.initials: M
authors.lastname: Vaillancourt
authors.forename: E
authors.initials: E
authors.lastname: Cohen
authors.forename: C
authors.initials: C
authors.lastname: Pargellis
authors.forename: C
authors.initials: C
authors.lastname: Yoakim
authors.forename: P C
authors.initials: PC
authors.lastname: Anderson
mesh_terms: D019380:Anti-HIV Agents / Q000494:pharmacology*; D004338:Drug Combinations; D004353:Drug Evaluation, Preclinical; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects*; D015498:HIV-2 / Q000187:drug effects; D006801:Humans; D019829:Nevirapine; D011725:Pyridines / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology*; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology; D015302:Simian Immunodeficiency Virus / Q000187:drug effects; D014633:Valine / Q000031:analogs & derivatives* / Q000494:pharmacology; D014779:Virus Replication / Q000187:drug effects
chemical_list: D019380:Anti-HIV Agents; D004338:Drug Combinations; D017320:HIV Protease Inhibitors; D011725:Pyridines; D011804:Quinolines; D018894:Reverse Transcriptase Inhibitors; C107199:palinavir; D019829:Nevirapine; D014633:Valine