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Inhibition of in Vitro and in Vivo Hiv Replication By a Distamycin Analogue That Interferes With Chemokine Receptor Function - a Candidate For Chemotherapeutic and Microbicidal Application

  1. Author:
    Howard, O. M. Z.
    Oppenheim, J. J.
    Hollingshead, M. G.
    Covey, J. M.
    Bigelow, J.
    McCormack, J. J.
    Buckheit, R. W.
    Clanton, D. J.
    Turpin, J. A.
    Rice, W. G.
    1. Year: 1998
  1. Journal: Journal of Medicinal Chemistry
    1. 41
    2. 13
    3. Pages: 2184-2193
  2. Type of Article: Article
  1. Abstract:

    Select chemokine receptors act as coreceptors for HIV-1 entry into human cells and represent targets for antiviral therapy. In this report we describe a distamycin analogue, 2,2'-[4,4'-[[aminocarbonyl]amino]bis[N,4'-di[pryrrole-2-carboxamide- 1,1'-dimethyl]]-6,8-naphthalenedisulfonic acid] hexasodium salt (NSC 651016), that selectively inhibited chemokine binding to CCR5, CCR3, CCRl,and CXCR4, but not to CXCR2 or CCR2b, and blocked chemokine-induced calcium flux. Inhibition was not due to nonspecific charge interactions at the cell surface, but was based on a specific competition for the ligand receptor interaction sites since the inhibitory effect was specific for some but not all chemoattractant receptors. NSC 651016 inhibited in vitro replication of a wide range of HIV-1 isolates, as well as HIV-2 and SIV, and exhibited in vivo anti-HIV-1 activity in a murine model. In contrast, a distamycin analogue with similar structure and charge and the monomeric form of NSC 651016 demonstrated no inhibitory effects. These data demonstrate that molecules which interfere with HIV-1 entry into cells by targeting specific chemokine coreceptors can provide a viable approach to anti-HIV-1 therapy. NSC 651016 represents an attractive candidate for the chemotherapeutic treatment of HIV-1 infection and as a microbicide to prevent the sexual transmisssion of HIV-1. Moreover, NSC 651016 can serve as a template for medicinal chemical modifications leading to more effective antivirals. [References: 41]

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