A solanesol-derived scaffold for multimerization of bioactive peptides.
A flexible molecular scaffold bearing varying numbers of terminal alkyne groups was synthesized in five steps from solanesol. R(CO)-MSH(4)-NH(2) ligands, which have a relatively low affinity for binding at the human melanocortin 4 receptor (hMC4R), were prepared by solid phase synthesis and were N-terminally acylated with 6-azidohexanoic acid. Multiple copies of the azide N(3)(CH(2))(5)(CO)-MSH(4)-NH(2) were attached to the alkyne-bearing, solanesol-derived molecular scaffold via the copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction. Control studies showed that the binding affinity of the triazole-containing ligand, CH(3)(CH(2))(3)(C(2)N(3))(CH(2))(5)(CO)-MSH(4)-NH(2), was not significantly diminished relative to the corresponding parental ligand, CH(3)(CO)-MSH(4)-NH(2). In a competitive binding assay with a Eu-labeled probe based on the superpotent ligand NDP-alpha-MSH, the monovalent and multivalent constructs appear to bind to hMC4R as monovalent species. In a similar assay with a Eu-labeled probe based on MSH(4), modest increases in binding potency with increased MSH(4) content per scaffold were observed.
Alleti
Ramesh
R
Department of Chemistry and Biochemistry, University of Arizona, Tucson, Arizona 85721-0041, USA.
Rao
Venkataramanarao
V
Xu
Liping
L
Gillies
Robert J
RJ
Mash
Eugene A
EA
D000480:Alkynes / Q000138:chemical synthesis* / Q000737:chemistry; D001386:Azides / Q000737:chemistry; D001665:Binding Sites; D002384:Catalysis; D003300:Copper / Q000737:chemistry; D003500:Cyclization; D005063:Europium / Q000737:chemistry; D006801:Humans; D008024:Ligands; D015394:Molecular Structure; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000737:chemistry; D010455:Peptides / Q000138:chemical synthesis* / Q000737:chemistry; D044105:Receptor, Melanocortin, Type 4 / Q000737:chemistry; D013729:Terpenes / Q000737:chemistry*
D000480:Alkynes; D001386:Azides; D008024:Ligands; C470072:MC4R protein, human; D009942:Organometallic Compounds; D010455:Peptides; D044105:Receptor, Melanocortin, Type 4; D013729:Terpenes; D005063:Europium; D003300:Copper; C017719:solanesol