title: Binding of ALX40-4C to APJ, a CNS-based receptor, inhibits its utilization as a co-receptor by HIV-1.
abstract: APJ, a G protein-coupled seven-transmembrane receptor, has been shown to serve as a co-receptor for the entry of human immunodeficiency virus type 1 (HIV-1), and it is dramatically expressed in central nervous system (CNS)-based cells. ALX40-4C was identified as a small-molecule antagonist of the chemokine receptor CXCR4, which can specifically inhibit HIV-1 entry via this co-receptor. In this study, we demonstrated that ALX40-4C inhibited both APJ- and CXCR4/APJ-mediated cell membrane fusion in a dose-dependent manner. In competitive binding assays, (125)I-Apelin13 was replaced by ALX40-4C with an IC(50) of 2.9 microM, as compared with an IC(50) of 0.2 nM for Apelin13. Furthermore, ALX40-4C could block ligand-induced APJ internalization and signaling. ALX40-4C, as an antagonist to APJ, directly binds to and prevents use of APJ as a HIV-1 co-receptor. Thus, ALX-4C has potential utility for further elucidation of HIV-1 neuropathogenesis and therapy of HIV-1-induced encephalopathy.
authors.affiliation: The Dorrance H. Hamilton Laboratories, Thomas Jefferson University, Jefferson Medical College, Center for Human Virology, Division of Infectious Diseases, Department of Medicine, 1020 Locust Street, Suite 329, Philadelphia, PA 19107, USA.
authors.forename: Naiming
authors.initials: N
authors.lastname: Zhou
authors.forename: Jianhua
authors.initials: J
authors.lastname: Fang
authors.forename: Edward
authors.initials: E
authors.lastname: Acheampong
authors.forename: Muhammad
authors.initials: M
authors.lastname: Mukhtar
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Pomerantz
mesh_terms: D000075244:Apelin Receptors; D001667:Binding, Competitive / Q000187:drug effects; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002490:Central Nervous System / Q000378:metabolism*; D065127:Dopamine D2 Receptor Antagonists; D004306:Dose-Response Relationship, Immunologic; D015699:HIV Envelope Protein gp120 / Q000378:metabolism; D015497:HIV-1 / Q000378:metabolism*; D006801:Humans; D008561:Membrane Fusion / Q000187:drug effects; D009842:Oligopeptides / Q000378:metabolism / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects; D019718:Receptors, CXCR4 / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled
chemical_list: C104575:APLNR protein, human; D000075244:Apelin Receptors; D065127:Dopamine D2 Receptor Antagonists; D015699:HIV Envelope Protein gp120; C094365:N-alpha-acetyl-nona-D-arginine amide acetate; D009842:Oligopeptides; D019718:Receptors, CXCR4; D017448:Receptors, Dopamine D2; D043562:Receptors, G-Protein-Coupled