Squalene-derived flexible linkers for bioactive peptides.
A regiochemical and stereochemical mixture of flexible linkers bearing terminal azide functionality was synthesized in two steps from squalene and was used to connect two high affinity NDP-alpha-MSH ligands or two low affinity MSH(4) ligands. The ligands were N-terminally acylated using N-hydroxysuccinimidoyl 5-hexynoate and were subsequently attached to the linker via copper-catalyzed 'click' 3+2 cyclization of the azide and alkyne moieties. In vitro biological evaluations showed that the binding affinity to the human melanocortin 4 receptor was not diminished for most linker-ligand combinations relative to the corresponding parental ligand. Statistical and cooperative binding effects were observed for dimeric constructs containing the low affinity ligand MSH(4), but not for dimeric NDP-alpha-MSH constructs, presumably due to slow off rates for this high affinity ligand.
Jagadish
Bhumasamudram
B
Department of Chemistry, University of Arizona, Tucson, AZ 85721-0041, USA.
Sankaranarayanan
Rajesh
R
Xu
Liping
L
Richards
Reyniak
R
Vagner
Josef
J
Hruby
Victor J
VJ
Gillies
Robert J
RJ
Mash
Eugene A
EA
D000480:Alkynes / Q000737:chemistry; D000595:Amino Acid Sequence; D001386:Azides / Q000737:chemistry; D001665:Binding Sites; D002384:Catalysis; D002851:Chromatography, High Pressure Liquid; D003300:Copper / Q000737:chemistry; D003500:Cyclization; D019281:Dimerization; D006801:Humans; D008024:Ligands; D013058:Mass Spectrometry; D008969:Molecular Sequence Data; D010455:Peptides / Q000138:chemical synthesis / Q000494:pharmacology*; D044105:Receptor, Melanocortin, Type 4 / Q000187:drug effects* / Q000378:metabolism; D013185:Squalene / Q000031:analogs & derivatives*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013388:Succinimides / Q000737:chemistry; D000521:alpha-MSH / Q000031:analogs & derivatives / Q000378:metabolism
D000480:Alkynes; D001386:Azides; D008024:Ligands; D010455:Peptides; D044105:Receptor, Melanocortin, Type 4; D013388:Succinimides; D000521:alpha-MSH; C046781:N-hydroxysuccinimide suberic acid ester; D003300:Copper; D013185:Squalene