Squalene-derived flexible linkers for bioactive peptides
| Autor: | Rajesh Sankaranarayanan, Reyniak Richards, Robert J. Gillies, Bhumasamudram Jagadish, Victor J. Hruby, Josef Vagner, Eugene A. Mash, Liping Xu |
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| Rok vydání: | 2007 |
| Předmět: |
Squalene
Azides Stereochemistry Molecular Sequence Data Clinical Biochemistry Succinimides Pharmaceutical Science Peptide Ligands Biochemistry Catalysis Mass Spectrometry Article Structure-Activity Relationship chemistry.chemical_compound Drug Discovery Humans Structure–activity relationship Amino Acid Sequence Binding site Molecular Biology Chromatography High Pressure Liquid chemistry.chemical_classification Binding Sites Organic Chemistry Cooperative binding Stereoisomerism Ligand (biochemistry) chemistry Cyclization alpha-MSH Alkynes Click chemistry Receptor Melanocortin Type 4 Molecular Medicine Azide Peptides Dimerization Linker Copper hormones hormone substitutes and hormone antagonists |
| Zdroj: | Bioorganic & Medicinal Chemistry Letters. 17:3310-3313 |
| ISSN: | 0960-894X |
| DOI: | 10.1016/j.bmcl.2007.04.001 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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