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Antimicrobial Agents and Chemotherapy, June 1998, p. 1340-1345, Vol. 42, No. 6
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

S-1153 Inhibits Replication of Known Drug-Resistant Strains of Human Immunodeficiency Virus Type 1

Tamio Fujiwara,1,* Akihiko Sato,1 Mohamed El-Farrash,1,dagger Shigeru Miki,1 Kenji Abe,1 Yoshitaka Isaka,1 Makoto Kodama,1 Yaming Wu,2 Lan Bo Chen,3 Hiroshi Harada,1 Hirohiko Sugimoto,1 Masakazu Hatanaka,1 and Yorio Hinuma1

Shionogi Research Laboratories, Shionogi & Co. Ltd., 5-12-4, Sagisu Fukushima-ku Osaka 553 Japan1; Shionogi BioResearch Corp., Lexington, Massachusetts 021732; and Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 021153

Received 2 October 1997/Returned for modification 25 November 1997/Accepted 13 March 1998

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.

* Corresponding author. Mailing address: Shionogi Institute for Medical Science, Shionogi & Co., Ltd., 2-5-1 Mishima, Settsu-shi, 566-0022, Japan. Phone: 81-6-382-2612. Fax: 81-6-382-2598. E-mail: tamio.fujiwara{at}shionogi.co.jp.

dagger Present address: Mansoura University Faculty of Medicine Department of Microbiology and Immunology, Mansoura, Egypt.

Antimicrobial Agents and Chemotherapy, June 1998, p. 1340-1345, Vol. 42, No. 6
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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