AIDS (acquired immune deficiency syndrome) is a condition that occurs in the advanced stages of human immunodeficiency virus (HIV) infection. AIDS can lead to a wide variety of neurological disorders such as HIV- associated dementia and neuropathic pain. These associated neurological disorders are collectively referred to as neuroAIDS. HIV infection is facilitated by co-receptors located on the surface of immune cells. One such co-receptor is the chemokine receptor CXCR4. This receptor is the entry receptor for the X4 virus, which emerges later in disease progression and has been associated with a more rapid progression to AIDS. Studies have shown that activation of the mu opioid receptor (MOR) elevates the expression of CXCR4, thus enhancing viral invasion and a more rapid progression to neuroAIDS. This correlation suggests crosstalk between these two receptors; however, the mechanism of this cross-talk is not very well understood. Therefore, to explore the possibility of one of these mechanisms, that is, formation of MOR-CXCR4 heterodimers, we have designed a series of novel bivalent probes containing both the MOR antagonist naltrexone and the CXCR4 antagonist It1t to inhibit both receptors synergistically. These ligands and their corresponding monovalent controls have been synthesized in reasonable yields through synthetic routes established in our lab. To understand how these bivalent ligands may interact with the MOR-CXCR4 heterodimer, biological studies including binding affinity, functional activity, and HIV-1 viral invasion assays have been employed. Additionally, a molecular model of the putative heterodimer has been constructed and docked with the bivalent probes to better understand how these probes may be synergistically interacting with the receptors.

Bivalent probes to elucidate the mechanism of opioid enhanced neuroAIDS

255th National Meeting (2018)

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