title: Linear scaffolds for multivalent targeting of melanocortin receptors.
abstract: Molecules bearing one, two, three, or four copies of the tetrapeptide His-dPhe-Arg-Trp were attached to scaffolds based on ethylene glycol, glycerol, and d-mannitol by means of the copper-assisted azide-alkyne cyclization. The abilities of these compounds to block binding of a probe at the melanocortin 4 receptor were evaluated using a competitive binding assay. All of the multivalent molecules studied exhibited 30- to 40-fold higher apparent affinites when compared to a monovalent control. These results are consistent with divalent binding to receptor dimers. No evidence for tri- or tetravalent binding was obtained. Differences in the interligand spacing required for divalent binding, as opposed to tri- or tetravalent binding, may be responsible for these results.
authors.affiliation: Department of Chemistry and Biochemistry, University of Arizona, Tucson, Arizona 85721-0041, USA. emash@email.arizona.edu.
authors.forename: Dilani Chathurika
authors.initials: DC
authors.lastname: Dehigaspitiya
authors.forename: Bobbi L
authors.initials: BL
authors.lastname: Anglin
authors.forename: Kara R
authors.initials: KR
authors.lastname: Smith
authors.forename: Craig S
authors.initials: CS
authors.lastname: Weber
authors.forename: Ronald M
authors.initials: RM
authors.lastname: Lynch
authors.forename: Eugene A
authors.initials: EA
authors.lastname: Mash
mesh_terms: D000480:Alkynes / Q000737:chemistry; D000595:Amino Acid Sequence; D001386:Azides / Q000737:chemistry; D001667:Binding, Competitive; D003500:Cyclization; D019855:Ethylene Glycol / Q000737:chemistry / Q000378:metabolism; D005990:Glycerol / Q000737:chemistry / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008353:Mannitol / Q000737:chemistry / Q000378:metabolism; D009842:Oligopeptides / Q000737:chemistry* / Q000378:metabolism*; D055503:Protein Multimerization; D044105:Receptor, Melanocortin, Type 4 / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D000480:Alkynes; D001386:Azides; D009842:Oligopeptides; D044105:Receptor, Melanocortin, Type 4; D008353:Mannitol; D019855:Ethylene Glycol; D005990:Glycerol