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Antimicrobial Agents and Chemotherapy, July 2009, p. 2940-2948, Vol. 53, No. 7
0066-4804/09/$08.00+0     doi:10.1128/AAC.01727-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

The Novel CXCR4 Antagonist KRH-3955 Is an Orally Bioavailable and Extremely Potent Inhibitor of Human Immunodeficiency Virus Type 1 Infection: Comparative Studies with AMD3100{triangledown}

Tsutomu Murakami,1,{dagger} Sei Kumakura,2,{dagger} Toru Yamazaki,2 Reiko Tanaka,3 Makiko Hamatake,1 Kazu Okuma,3,{ddagger} Wei Huang,4 Jonathan Toma,4 Jun Komano,1 Mikiro Yanaka,2,§ Yuetsu Tanaka,3 and Naoki Yamamoto1*

AIDS Research Center, National Institute of Infectious Diseases, Tokyo 162-8640,1 Biomedical Research Laboratories, Kureha Corporation, Tokyo 169-8503,2 Department of Immunology, Graduate School and Faculty of Medicine, University of the Ryukyus, Nakagami, Okinawa 903-0215, Japan,3 Monogram Biosciences, South San Francisco, California 940804

Received 30 December 2008/ Returned for modification 12 February 2009/ Accepted 7 May 2009

The previously reported CXCR4 antagonist KRH-1636 was a potent and selective inhibitor of CXCR4-using (X4) human immunodeficiency virus type 1 (HIV-1) but could not be further developed as an anti-HIV-1 agent because of its poor oral bioavailability. Newly developed KRH-3955 is a KRH-1636 derivative that is bioavailable when administered orally with much more potent anti-HIV-1 activity than AMD3100 and KRH-1636. The compound very potently inhibits the replication of X4 HIV-1, including clinical isolates in activated peripheral blood mononuclear cells from different donors. It is also active against recombinant X4 HIV-1 containing resistance mutations in reverse transcriptase and protease and envelope with enfuvirtide resistance mutations. KRH-3955 inhibits both SDF-1{alpha} binding to CXCR4 and Ca2+ signaling through the receptor. KRH-3955 inhibits the binding of anti-CXCR4 monoclonal antibodies that recognize the first, second, or third extracellular loop of CXCR4. The compound shows an oral bioavailability of 25.6% in rats, and its oral administration blocks X4 HIV-1 replication in the human peripheral blood lymphocyte-severe combined immunodeficiency mouse system. Thus, KRH-3955 is a new promising agent for HIV-1 infection and AIDS.

* Corresponding author. Mailing address: AIDS Research Center, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo 162-8640, Japan. Phone: 81-3-5285-1111, ext. 2302. Fax: 81-3-5285-1165. E-mail: nyama{at}nih.go.jp

{triangledown} Published ahead of print on 18 May 2009.

{dagger} T.M. and S.K. contributed equally to this work.

{ddagger} Present address: Department of Safety Research on Blood and Biological Products, National Institute of Infectious Diseases, Gakuen 4-7-1, Musashimurayama-shi, Tokyo 208-0011, Japan.

§ Present address: Kureha Special Laboratory Co., Ltd., Fukushima 974-8232, Japan.

Antimicrobial Agents and Chemotherapy, July 2009, p. 2940-2948, Vol. 53, No. 7
0066-4804/09/$08.00+0     doi:10.1128/AAC.01727-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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