S-1153 inhibits replication of known drug-resistant strains of human immunodeficiency virus type 1.
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.
Fujiwara
T
T
Shionogi Research Laboratories, Shionogi & Co. Ltd., Osaka, Japan. tamio.fujiwara@shionogi.co.jp
Sato
A
A
el-Farrash
M
M
Miki
S
S
Abe
K
K
Isaka
Y
Y
Kodama
M
M
Wu
Y
Y
Chen
L B
LB
Harada
H
H
Sugimoto
H
H
Hatanaka
M
M
Hinuma
Y
Y
D000818:Animals; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000494:pharmacology*; D002478:Cells, Cultured; D004352:Drug Resistance, Microbial; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D013601:T-Lymphocytes; D014779:Virus Replication / Q000187:drug effects*
D019380:Anti-HIV Agents; D007093:Imidazoles; C113604:S 1153