Bivalent Ligand Aiming Putative Mu Opioid Receptor and Chemokine Receptor CXCR4 Dimers in Opioid Enhanced HIV-1 Entry.

A bivalent compound featuring both a mu opioid receptor (MOR) and a CXCR4 antagonist pharmacophore (naltrexone and IT1t) was designed and synthesized. Further binding and functional studies demonstrated acting as a MOR and a CXCR4 dual antagonist with reasonable binding affinities at both receptors. Furthermore, compound seemed more effective than a combination of IT1t and naltrexone in inhibiting HIV entry at the presence of morphine. Additional molecular modeling results suggested that may bind with the putative MOR-CXCR4 heterodimer to induce its anti-HIV activity. Collectively, bivalent ligand may serve as a promising lead to develop chemical probes targeting the putative MOR-CXCR4 heterodimer in comprehending opioid exacerbated HIV-1 invasion.