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Squalene-derived flexible linkers for bioactive peptides.

ABSTRACT: 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.

SUBMITTER: Jagadish B

PROVIDER: S-EPMC2033335 | biostudies-literature | 2007 Jun

REPOSITORIES: biostudies-literature

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Squalene-derived flexible linkers for bioactive peptides.

Jagadish Bhumasamudram B Sankaranarayanan Rajesh R Xu Liping L Richards Reyniak R Vagner Josef J Hruby Victor J VJ Gillies Robert J RJ Mash Eugene A EA

Bioorganic & medicinal chemistry letters 20070406 12

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 bindi ...[more]

PMID: 17448660

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