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.

Computational Characterization of Structural Role of the Non-active Site Mutation M36I of Human Immunodeficiency Virus Type 1 Protease

“…Nine PR inhibitors (PIs) have been approved by the Food and Drug Administration (FDA). [4][5][6][7][8][9][10][11][12] Nevertheless, the currently available PIs were developed and tested only against subtype B PRs. Some studies have shown that non-subtype B viruses show different responses than the responses of subtype B virus Abbreviations used: HIV-1, human immunodeficiency virus type 1; PR, protease; PI, protease inhibitor; NFV, nelfinavir; FDA, Food and Drug Administration; WT, wild-type; MD, molecular dynamics.…”

Insights into HIV-1 pathogenesis through drug discovery: 30 years of basic research and concerns for the future

“…In this way, PIs resembled NRTIs and NNRTIs. However, initial single amino acid mutations resulted in a modest change (less than a factor of 5) in drug sensitivity in vitro [76][77][78][79] yet, secondary mutations lead to high-level drug resistance and considerable cross-resistance to other protease inhibitors [75,80,81]. This was mirrored in vivo when two PIs did not protect against HIV-1 burden in PI-experienced patients [75,80,81].…”

Resistant mechanism against nelfinavir of subtype C human immunodeficiency virus type 1 proteases

“…Therefore, HIV-1 PR is an attractive target for anti-HIV-1 drugs. Today, nine protease inhibitors [6][7][8][9][10][11][12][13][14] have been approved by the FDA and have successfully lowered the death rate owing to AIDS in developed countries during the past decade. However, the currently available protease inhibitors were developed and tested only against subtype B PRs, and HIV-1 frequently acquires the resistance to these inhibitors through specific mutations due to the high polymorphism and adaptability of the protease [15][16][17][18][19].…”