Figure 6.

Summary of DLS and TAK779 activities on HIV-1 propagation and CCR5 Function. While the current and most efficient treatment modalities for the treatment of HIV-1+ patients include reverse transcriptase and protease inhibitors, viruses are now developing resistance to one or more agents. Despite the efficacy of these agents, there is still dire need to discover new anti-HIV agents to inhibit viral infectivity. CXCR4 and CCR5 are the major co-receptors for HIV-1 entry into the CD4 positive cells. Thus, it would appear that chemokine receptors, more specifically here CCR5, are attractive targets to block HIV-1 binding, fusion and infectivity. Several potent chemokine receptor antagonists have been developed and are being utilized in clinical studies. TAK779 is a very selective CCR5 blocking agent and has been shown to block HIV-1 entry through CCR5-bearing cells and also blocks CCR5 function and signaling. We have found that the GHS-R1a antagonist, DLS, exhibits some modest blocking effects on CCR5 ligand binding and signaling, with the greatest effects being observed on RANTES binding and activity. Moreover, DLS can inhibit CCR5-trophic HIV-1 infectivity in CCR5+ immune cells, although it is significantly less potent than the CCR5 selective antagonist, TAK779, which is currently being utilized in clinical trials. While DLS may possess some modest antagonist activity for CCR5, the primary finding focused on in this manuscript is that DLS, initially thought to be a highly selective antagonist for the ghrelin receptor, GHS-R1a, appears to be promiscuous and may have some effects on other G-protein coupled receptors (GPCRs) such as chemokine receptors.