S-1153 inhibits replication of known drug-resistant strains of human immunodeficiency virus type 1

Abstract

S-1153 is a new imidazole compound that inhibits human immunodeficiency virus (HIV) type 1 (HIV-1) replication by acting as a nonnucleoside reverse transcriptase inhibitor (NNRTI). This compound inhibits replication of HIV-1 strains that are resistant to nucleoside and nonnucleoside reverse transcriptase inhibitors. S-1153 has a 50% effective concentration in the range of 0.3 to 7 ng/ml for strains with single amino acid substitutions that cause NNRTI resistance, including the Y181C mutant, and also has potent activity against clinical isolates. The emergence of S-1153-resistant variants is slower than that for nevirapine, and S-1153-resistant variants contained at least two amino acid substitutions, including F227L or L234I. S-1153-resistant variants are still sensitive to the nucleoside reverse transcriptase inhibitors zidovudine (AZT) and lamivudine. In a mouse and MT-4 (human T-cell line) in vivo HIV replication model, S-1153 and AZT administered orally showed a marked synergy for the inhibition of HIV-1 replication. S-1153 shows a significant accumulation in lymph nodes, where most HIV-1 infection is thought to occur. S-1153 may be an appropriate candidate for two-to three-drug combination therapy for HIV infection.

FIG. 1

Chemical structure of S-1153.

FIG. 2

Inhibition of HIV-1 replication by S-1153 in the mouse–MT-4 cell model. The method used was the same as that published previously (28). AZT and S-1153 were dissolved or were suspended in 0.5% methylcellulose and were administered orally immediately after the injection of 5 × 10⁷ HIV-infected MT-4 cells in 0.3 ml of phosphate-buffered saline into the peritoneal cavities of BALB/c mice. The percent inhibition of viral growth by the drugs 24 h after transplantation is the mean for three mice. (A) Dose-dependent inhibition of HIV-1 replication by S-1153 or AZT alone. (B) Inhibition of HIV-1 replication by the combination of S-1153 and AZT.