SMALL-MOLECULE INHIBITOR OF HIV-1 CELL-FUSION BLOCKS CHEMOKINE RECEPTOR-MEDIATED FUNCTION

The intersection of the HIV and the chemokine fields began with the ob servation that HIV entry into cells could be blocked by certain chemok ines. Subsequent work showed that HIV entry is dependent on the presen ce of specific chemokine receptors, These observations led us to evalu ate a series of compounds, ureido analogs of distamycin previously rep orted to block HIV entry into cells in vitro, for chemokine antagonist activity, One of the distamycin analogs, [N,4'-di[pyrrole-2-carboxami de-1,1'-dimethyl]]-6,8 napthalenedisulfonic acid] hexasodium salt (NSC 651016), is shown here to inhibit syncytia formation and cell fusion, Mechanistic studies showed that this inhibition was not due to confor mational changes in gp120-gp41 induced by target cell CDP and chemokin e co-receptor and was therefore not due to interference with binding o f HIV-1. Additional mechanistic studies demonstrated that NSC 651016 i nhibited chemokine binding to specific chemokine receptors, induced CX CR4 and CCR5 receptor internalization, and inhibited chemokine-induced chemotaxis by macrophage inflammatory protein (MIP)-1 alpha, MIP-1 be ta, RANTES, and stromal-derived factor-1 alpha but not monocyte chemot actic protein-1, Thus, we describe a novel compound that inhibits in v ivo replication of HIV-1 by down-regulation of coreceptors, These data lead us to propose that NSC 651016 may have in vivo anti-inflammatory activity.