title: Analysis of the mechanism by which the small-molecule CCR5 antagonists SCH-351125 and SCH-350581 inhibit human immunodeficiency virus type 1 entry.
abstract: Human immunodeficiency virus type 1 (HIV-1) entry is mediated by the consecutive interaction of the envelope glycoprotein gp120 with CD4 and a coreceptor such as CCR5 or CXCR4. The CCR5 coreceptor is used by the most commonly transmitted HIV-1 strains that often persist throughout the course of infection. Compounds targeting CCR5-mediated entry are a novel class of drugs being developed to treat HIV-1 infection. In this study, we have identified the mechanism of action of two inhibitors of CCR5 function, SCH-350581 (AD101) and SCH-351125 (SCH-C). AD101 is more potent than SCH-C at inhibiting HIV-1 replication in primary lymphocytes, as well as viral entry and gp120 binding to cell lines. Both molecules also block the binding of several anti-CCR5 monoclonal antibodies that recognize epitopes in the second extracellular loop of CCR5. Alanine mutagenesis of the transmembrane domain of CCR5 suggests that AD101 and SCH-C bind to overlapping but nonidentical sites within a putative ligand-binding cavity formed by transmembrane helices 1, 2, 3, and 7. We propose that the binding of small molecules to the transmembrane domain of CCR5 may disrupt the conformation of its extracellular domain, thereby inhibiting ligand binding to CCR5.
authors.affiliation: Microbiology and Immunology Department, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
authors.forename: Fotini
authors.initials: F
authors.lastname: Tsamis
authors.forename: Svetlana
authors.initials: S
authors.lastname: Gavrilov
authors.forename: Francis
authors.initials: F
authors.lastname: Kajumo
authors.forename: Christoph
authors.initials: C
authors.lastname: Seibert
authors.forename: Shawn
authors.initials: S
authors.lastname: Kuhmann
authors.forename: Tom
authors.initials: T
authors.lastname: Ketas
authors.forename: Alexandra
authors.initials: A
authors.lastname: Trkola
authors.forename: Anadan
authors.initials: A
authors.lastname: Palani
authors.forename: John W
authors.initials: JW
authors.lastname: Clader
authors.forename: Jayaram R
authors.initials: JR
authors.lastname: Tagat
authors.forename: Stuart
authors.initials: S
authors.lastname: McCombie
authors.forename: Bahige
authors.initials: B
authors.lastname: Baroudy
authors.forename: John P
authors.initials: JP
authors.lastname: Moore
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Sakmar
authors.forename: Tatjana
authors.initials: T
authors.lastname: Dragic
mesh_terms: D000595:Amino Acid Sequence; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000378:metabolism; D065100:CCR5 Receptor Antagonists; D015496:CD4-Positive T-Lymphocytes / Q000821:virology; D002478:Cells, Cultured; D003497:Cyclic N-Oxides / Q000494:pharmacology*; D015699:HIV Envelope Protein gp120 / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects* / Q000472:pathogenicity*; D006801:Humans; D008561:Membrane Fusion; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010091:Oximes; D010880:Piperidines; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology*; D019713:Receptors, CCR5 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D014779:Virus Replication
chemical_list: D000911:Antibodies, Monoclonal; D065100:CCR5 Receptor Antagonists; D003497:Cyclic N-Oxides; D015699:HIV Envelope Protein gp120; D010091:Oximes; D010880:Piperidines; D011725:Pyridines; D019713:Receptors, CCR5; C438583:Ancriviroc