Structure-Based Design and Development of Chemical Probes Targeting Putative MOR-CCR5 Heterodimers to Inhibit Opioid Exacerbated HIV‑1 Infectivity

Crystal structures of ligand-bound
G-protein-coupled receptors
provide tangible templates for rationally designing molecular probes.
Herein, we report the structure-based design, chemical synthesis,
and biological investigations of bivalent ligands targeting putative
mu opioid receptor C–C motif chemokine ligand 5 (MOR-CCR5)
heterodimers. The bivalent ligand VZMC013 possessed nanomolar
level binding affinities for both the MOR and CCR5, inhibited CCL5-stimulated
calcium mobilization, and remarkably improved anti-HIV-1BaL activity over previously reported bivalent ligands. VZMC013 inhibited viral infection in TZM-bl cells coexpressing CCR5 and
MOR to a greater degree than cells expressing CCR5 alone. Furthermore, VZMC013 blocked human immunodeficiency virus (HIV)-1 entry
in peripheral blood mononuclear cells (PBMC) cells in a concentration-dependent
manner and inhibited opioid-accelerated HIV-1 entry more effectively
in phytohemagglutinin-stimulated PBMC cells than in the absence of
opioids. A three-dimensional molecular model of VZMC013 binding to the MOR-CCR5 heterodimer complex is constructed to elucidate
its mechanism of action. VZMC013 is a potent chemical
probe targeting MOR-CCR5 heterodimers and may serve as a pharmacological
agent to inhibit opioid-exacerbated HIV-1 entry.