title: Antiviral and resistance studies of AG1343, an orally bioavailable inhibitor of human immunodeficiency virus protease.
abstract: AG1343 ([3S-(3R*,4aR*,8aR*,2'S*,3'S*)]-2-[2' hydroxy-3'-phenylthiomethyl-4'-aza-5'-oxo-5'-(2''-methyl-3''-hydro xy-phenyl) pentyl]-decahydroiso-quinoline-3-N-t-butylcarboxamide methanesulfonic acid) is a selective, nonpeptidic inhibitor of human immunodeficiency virus (HIV) protease (Ki = 2 nM) that was discovered by protein structure-based drug design methodologies. AG1343 was effective against the replication of several laboratory and clinical HIV type 1 (HIV-1) or HIV-2 isolates including pyridinone- and zidovudine-resistant strains, with 50% effective concentrations ranging from 9 to 60 nM. In reversibility studies, inhibition of gag (p55) proteolytic processing in HIV-1 particles from cells treated with AG1343 was maintained for up to 36 h after drug removal. The ability of virus to develop resistance to AG1343 was studied by serial passage of HIV-1 NL4.3 in the presence of increasing concentrations of drug. After 28 passages, a variant with a 30-fold reduction in susceptibility to AG1343 was isolated. Molecular analysis of the protease from this variant indicated a double change from a Met to Ile at residue 46 and an Ile to Val or Ala at residue 84 (M46I+I84V, A). Consistent with these findings, reductions in susceptibility were observed for recombinant viruses constructed to contain the single I84V change or the double M46I+I84V substitutions. Resistance, however, was not detected for recombinant viruses containing other key mutations in HIV-1 protease, including a Val to Ile change at residue 32 or a Val to Ala or Phe at residue 82. The potent anti-HIV activity of AG1343 against several isolates suggests that AG1343 should perform well during ongoing human phase II clinical trials.
authors.affiliation: Department of Pharmacology, Agouron Pharmaceuticals, Inc., San Diego, CA 92121, USA.
authors.forename: A K
authors.initials: AK
authors.lastname: Patick
authors.forename: H
authors.initials: H
authors.lastname: Mo
authors.forename: M
authors.initials: M
authors.lastname: Markowitz
authors.forename: K
authors.initials: K
authors.lastname: Appelt
authors.forename: B
authors.initials: B
authors.lastname: Wu
authors.forename: L
authors.initials: L
authors.lastname: Musick
authors.forename: V
authors.initials: V
authors.lastname: Kalish
authors.forename: S
authors.initials: S
authors.lastname: Kaldor
authors.forename: S
authors.initials: S
authors.lastname: Reich
authors.forename: D
authors.initials: D
authors.lastname: Ho
authors.forename: S
authors.initials: S
authors.lastname: Webber
mesh_terms: D000595:Amino Acid Sequence; D000998:Antiviral Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D004352:Drug Resistance, Microbial; D015683:Gene Products, gag / Q000378:metabolism; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D015498:HIV-2 / Q000187:drug effects*; D007546:Isoquinolines / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D008969:Molecular Sequence Data; D009340:Nefopam; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology; D019258:Saquinavir / Q000494:pharmacology; D013451:Sulfonic Acids / Q000494:pharmacology*; D015215:Zidovudine / Q000494:pharmacology
chemical_list: D000998:Antiviral Agents; D015683:Gene Products, gag; D017320:HIV Protease Inhibitors; D007546:Isoquinolines; D018894:Reverse Transcriptase Inhibitors; D013451:Sulfonic Acids; D015215:Zidovudine; D009340:Nefopam; D019258:Saquinavir