ANTIVIRAL AND RESISTANCE STUDIES OF AG1343, AN ORALLY BIOAVAILABLE INHIBITOR OF HUMAN-IMMUNODEFICIENCY-VIRUS PROTEASE

AG1343 ([3S-(3R, 4aR*, 8aR*, 2'S*, 3'S*)]-2-[2' hydroxy-3'-phenylthio methyl-4'-aza-5'-oxo-5'-(2 ''-methyl-3 tyl]-decahydroiso-quinoline-3-N -t-butylcarboxamide methanesulfonic acid) is a selective, nonpeptidic inhibitor of human immunodeficiency virus (HIV) protease (K-i = 2 nM) that was discovered by protein structure-based drug design methodologi es, AG1343 was effective against the replication of several laboratory and clinical HIV type 1 (HIV-1) or HIV-2 isolates including pyridinon e- 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 wit h AG1343 was maintained for up to 36 h after drug removal, The ability of virus to develop resistance to AG1343 was studied by serial passag e of HIV-1 NL4.3 in the presence of increasing concentrations of drug, After 28 passages, a variant with a 30-fold reduction in susceptibili ty to AG1343 was isolated, Molecular analysis of the protease from thi s variant indicated a double change from a Met to Ile at residue 46 an d an Ile to Val or Ala at residue 84 (M46I + I84V A), Consistent with these findings, reductions in susceptibility were observed for recombi nant viruses constructed to contain the single I84V change or the doub le M46I + I84V substitutions, Resistance, however, was not detected fo r 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 a t residue 82, The potent anti-HIV activity of AG1343 against several i solates suggests that AG1343 should perform well during ongoing human phase II clinical trials.