Structure-Based Design and Development of Chemical Probes Targeting Putative MOR-CCR5 Heterodimers to Inhibit Opioid Exacerbated HIV‑1 Infectivity
1753
unknown
Zugriff:
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-1 BaL 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.
Titel: |
Structure-Based Design and Development of Chemical Probes Targeting Putative MOR-CCR5 Heterodimers to Inhibit Opioid Exacerbated HIV‑1 Infectivity
|
---|---|
Autor/in / Beteiligte Person: | Boshi Huang (3080169) ; Huiqun Wang (5544422) ; Yi Zheng (113896) ; Mengchu Li (8108468) ; Guifeng Kang (9371741) ; Victor Barreto-de-Souza (9371735) ; Nima Nassehi (9371744) ; Pamela E. Knapp (8201928) ; Dana E. Selley (1448944) ; Kurt F. Hauser (8201931) ; Yan Zhang (8098) |
Link: | |
Veröffentlichung: | 1753 |
Medientyp: | unknown |
DOI: | 10.1021/acs.jmedchem.1c00408.s001 |
Schlagwort: |
|
Sonstiges: |
|