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FP-21399 blocks HIV envelope protein-mediated membrane fusion and concentrates in lymph nodes

Nature Biotechnology volume 15, pages 343–348 (1997)Cite this article

Abstract

The identification of fusin and other chemokine receptors as coreceptors for HIV-1 has renewed the interest in agents that may prevent viral entry. Polyanionic compounds such as dextran sulfate, curdlan sulfate, and suramin act on the V3 loop of the viral envelope and may prevent its interaction with fusin. These agents show activity against a wide range of HIV-1 strains, but have undesirable circulating half-life, bioavallability, and toxicity. We have developed a small molecule inhibitor of HIV-1 that has several advantages over these other agents. FP-21399 is a novel compound of the bis(disulfonaphthalene) dimethoxybenzene class that blocks entry of HIV into CD4+ cells and blocks fusion of infected and noninfected CD4+ cells. This compound only weakly inhibits binding of CD4 and gp120, at concentrations much greater than are required to block viral entry. Furthermore, FP-21399 can block the interaction between gp120 and antibodies directed against the V3 loop, but does not block binding of antibodies directed against the V4 loop. Animal studies demonstrate that FP-21399 is concentrated in lymph nodes, making It a promising compound for anti-HIV therapy. In SCID mice reconstituted with human immune cells, maintenance of HIV-1 infection was blocked by a 5-day treatment with low doses of FP-21399, suggesting that lymph node accumulation may contribute to antiviral activity. Finally, attempts to generate drug-resistant virus in cell culture resulted in only weakly resistant variants with IC90values that are much lower than concentrations of FP-21399 found in lymph nodes.

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Author notes

  1. Jeffrey C. Way: Corresponding author (e-mail: jway@fujipharm.com).

Authors and Affiliations

  1. Fuji ImmunoPharmaceuticals Corp., 125 Hartwell Ave., Lexington, MA, 02173

    Mitsunori Ono, Yumiko Wada, Yaming Wu, Hong Wang, Kin-Ming Lo, Naoto Yamaguchi, Beatrice Brunkhorst, John Wesolowski & Stephen Gillies

  2. Fuji Photo Film Co., Ltd., Research Laboratories, Ashigara, Minami-Ashigara, Kanagawa, 2250-01, Japan

    Ryoichi Nemori, Yumiko Jinbo, Hiroko Otomo & Isamu Itoh

  3. Dana Farber Cancer Institute, Harvard Medical School 44 Binney St., Boston, MA, 02115

    Lan Bo Chen

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Ono, M., Wada, Y., Wu, Y. et al. FP-21399 blocks HIV envelope protein-mediated membrane fusion and concentrates in lymph nodes. Nat Biotechnol 15, 343–348 (1997). https://doi.org/10.1038/nbt0497-343

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