title: Ligand selectivity of a synthetic CXCR4 mimetic peptide.
abstract: The chemokine receptor CXCR4 belongs to the family of seven-transmembrane G-protein coupled receptors (GPCRs). It is activated by its natural ligand SDF-1α. In addition, CXCR4, along with CCR5, serve as coreceptors during HIV-1 entry into its target cell. Recently, we introduced a CXCR4 mimetic peptide, termed CX4-M1, which presents the three extracellular loops (ECLs) of the receptor. CX4-M1 was shown to selectively bind to gp120 of X4-tropic, that is, CXCR4 using, HIV-1, as well as to peptides that present the V3-loops of these gp120 proteins. Furthermore, CX4-M1 selectively inhibits infection of cells with X4-tropic HIV-1. We have now adapted the sequence of the ECLs presented by CX4-M1 to the recently published crystal structure of CXCR4. The binding behavior, as well as the effect on HIV-1 infection, of the resulting peptide (CX4-Mc) was very similar to CX4-M1, validating retrospectively the original design of CX4-M1. A peptide presenting the ECLs of CCR5 (CR5-M), on the other hand, did neither bind to gp120 from X4-tropic HIV-1, nor did it inhibit infection of cells with X4-tropic HIV-1. Furthermore, we could show that CX4-M1, as well as CX4-Mc, but not CR5-M, are selectively recognized by anti-CXCR4 antibodies, bind to SDF-1α, and also inhibit SDF-1α signaling, extending the scope of selective functional CXCR4 mimicry through CX4-M1.
authors: Department of Chemistry and Pharmacy, University of Erlangen-Nurnberg, Schuhstrasse 19, 91052 Erlangen, Germany.
authors: Andrea
authors: A
authors: Groß
authors: Department of Chemistry and Pharmacy, University of Erlangen-Nurnberg, Schuhstrasse 19, 91052 Erlangen, Germany.
authors: Regine
authors: R
authors: Brox
authors: Institute of Medical Microbiology and Hygiene, University of Regensburg, Franz-Josef-Strauss-Allee 11, 93053 Regensburg, Germany.
authors: Dominik
authors: D
authors: Damm
authors: Department of Chemistry and Pharmacy, University of Erlangen-Nurnberg, Schuhstrasse 19, 91052 Erlangen, Germany.
authors: Nuška
authors: N
authors: Tschammer
authors: Institute of Medical Microbiology and Hygiene, University of Regensburg, Franz-Josef-Strauss-Allee 11, 93053 Regensburg, Germany.
authors: Barbara
authors: B
authors: Schmidt
authors: Department of Chemistry and Pharmacy, University of Erlangen-Nurnberg, Schuhstrasse 19, 91052 Erlangen, Germany. Electronic address: jutta.eichler@fau.de.
authors: Jutta
authors: J
authors: Eichler
mesh_terms: D019380:Anti-HIV Agents / Q000737:chemistry / Q000494:pharmacology; D000906:Antibodies / Q000276:immunology / Q000378:metabolism; D002460:Cell Line / Q000187:drug effects / Q000821:virology; D054377:Chemokine CXCL12 / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D015699:HIV Envelope Protein gp120 / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects* / Q000472:pathogenicity; D006801:Humans; D008024:Ligands; D018716:Molecular Mimicry; D009500:Neutralization Tests; D010455:Peptides / Q000737:chemistry / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology*; D019718:Receptors, CXCR4 / Q000276:immunology / Q000378:metabolism*
chemical_list: D019380:Anti-HIV Agents; D000906:Antibodies; C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; D015699:HIV Envelope Protein gp120; D008024:Ligands; D010455:Peptides; D019718:Receptors, CXCR4; C514793:gp120 protein, Human immunodeficiency virus 1
keywords: CXCL12/SDF-1α; CXCR4; GPCR; HIV-1; Peptide; Receptor mimic