A Study of Anti-HIV Compounds which Interfere the Virus Entry via Coreceptor CXCR4

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  • KANBARA Kenji
    Department of Microbiology and Immunology, Kagoshima University Dental School
  • FUJII Nobutaka
    Graduate School of Pharmaceutical Sciences, Kyoto University
  • NAKASHIMA Hideki
    Department of Microbiology and Immunology, Kagoshima University Dental School

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Other Title
  • HIV感染のコレセプター, CXCR4, を標的とした抗HIV薬の開発
  • 第73回 日本感染症学会総会 学術講演会座長 推薦論文 HIV感染のコレセプター,CXCR4,を標的とした抗HIV薬の開発
  • ダイ73カイ ニホン カンセンショウ ガッカイ ソウカイ ガクジュツ コウエンカイ ザチョウ スイセン ロンブン HIV カンセン ノ コレセプター CXCR4 オ ヒョウテキ ト シタ コウHIVヤク ノ カイハツ

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Abstract

T22 is an anti-HIV polypeptide which was synthesized with chemical modification from the horse shoe hemocytic polypeptides, polyphemusin II as a lead compound. T22 was found to block Ttropic HIV-1 entry into target cells as a CXCR4 antagonist. We synthesized T134, a small sized analog of T22 with reduced positive charges. T134 exhibited highly potent activity and significantly less cytotoxicity when compared to T22. It was shown that bicyclam AMD3100 and ALX40-4C are antagonists of CXCR4, and vMIP II which is coded chemokine in HHV8/ICSHV effects antagonistically both CXCR4 and CCR5. We examined the anti-HIV activity of these CXCR4 antagonists. All of them inhibit the binding of anti-CXCR4 antibody (12G5) to PBMC, but have no effect on the binding of anti-CCR5 antibody (2D7) except for vMIP II. vMIP II decreased the binding of both 12G5 and 2D7. In these compounds, T134 showed the most potency to anti-HIV activity. We also attempted to clarify the cross resistance between these antagonists, using HIV-1 resistant to AMD3100. T134, ALX40-4C and vMIP II are active against the AMD3100 resistant strain. This observation indicates the potential of using these the inhibitors as a new type of agent preventing HIV entry.

Journal

  • Kansenshogaku Zasshi

    Kansenshogaku Zasshi 74 (3), 237-244, 2000

    The Japanese Association for Infectious Diseases

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