title: Nonspanning bivalent ligands as improved surface receptor binding inhibitors of the cholera toxin B pentamer.
abstract: A series of bivalent ligands of varying length were synthesized to inhibit the receptor-binding process of cholera toxin. Competitive surface receptor binding assays showed that significant potency gains relative to the constituent monovalent ligands were achieved independently from the ability of the extended bivalent ligands to span binding sites within the toxin pentamer. Several models that could account for the unexpected improvement in IC(50) values are examined, taking into account crystallographic analysis of each ligand in complex with the toxin pentamer. Evidence is presented that steric blocking at the receptor binding surface may play a role. The results of our study suggest that the use of relatively short, "nonspanning" bivalent ligands, or monovalent ligands of similar topology and bulk may be an effective way of blocking the interaction of multimeric proteins with their cell surface receptors.
authors.affiliation: Department of Chemistry, University of Washington, Seattle, WA 98195, USA.
authors.forename: Jason C
authors.initials: JC
authors.lastname: Pickens
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Mitchell
authors.forename: Jiyun
authors.initials: J
authors.lastname: Liu
authors.forename: Xiaojian
authors.initials: X
authors.lastname: Tan
authors.forename: Zhongsheng
authors.initials: Z
authors.lastname: Zhang
authors.forename: Christophe L M J
authors.initials: CL
authors.lastname: Verlinde
authors.forename: Wim G J
authors.initials: WG
authors.lastname: Hol
authors.forename: Erkang
authors.initials: E
authors.lastname: Fan
mesh_terms: D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D000595:Amino Acid Sequence; D001667:Binding, Competitive; D002772:Cholera Toxin / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D018360:Crystallography, X-Ray; D020128:Inhibitory Concentration 50; D008024:Ligands; D008969:Molecular Sequence Data; D015394:Molecular Structure; D009598:Nitrophenylgalactosides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000577:Amides; D008024:Ligands; D010879:Piperazines; D011956:Receptors, Cell Surface; D009598:Nitrophenylgalactosides; D002772:Cholera Toxin