Solid-phase synthesis and biological activity of a thioether analogue of conotoxin G1.

TY - JOUR

T1 - Solid-phase synthesis and biological activity of a thioether analogue of conotoxin G1.

AU - Bondebjerg, Jon

AU - Grunnet, Morten

AU - Jespersen, Thomas

AU - Meldal, Morten

N1 - Keywords: Animals; Chromatography, High Pressure Liquid; Conotoxins; Cyclization; Female; Oocytes; Peptide Biosynthesis; Receptors, Nicotinic; Structure-Activity Relationship; Sulfides; Xenopus

PY - 2003

Y1 - 2003

N2 - A bicyclic thioether analogue of alpha-conotoxin G1, a neurotoxin found in the venom of cone snails, was synthesized on solid phase. Two successive intramolecular on-bead cyclizations between a cysteine residue and a chloroacetylated reduced peptide bond are the key steps in the synthesis. The first reduced peptide bond was introduced by a reductive alkylation with a 9-fluorenylmethoxycarbonyl protected amino aldehyde, and the second by coupling of a dipeptide building block containing an allyloxycarbonyl protected reduced peptide bond. The desired bicyclic product was obtained as a mixture of two isomers, which were evaluated for their ability to inhibit the muscular nicotinic acetylcholine receptor expressed in Xenopus oocytes. The two isomers were found to have IC(50) values (inhibitory activities) of 144 microM and 48 microM, compared to 0.18 microM for native conotoxin G1.

AB - A bicyclic thioether analogue of alpha-conotoxin G1, a neurotoxin found in the venom of cone snails, was synthesized on solid phase. Two successive intramolecular on-bead cyclizations between a cysteine residue and a chloroacetylated reduced peptide bond are the key steps in the synthesis. The first reduced peptide bond was introduced by a reductive alkylation with a 9-fluorenylmethoxycarbonyl protected amino aldehyde, and the second by coupling of a dipeptide building block containing an allyloxycarbonyl protected reduced peptide bond. The desired bicyclic product was obtained as a mixture of two isomers, which were evaluated for their ability to inhibit the muscular nicotinic acetylcholine receptor expressed in Xenopus oocytes. The two isomers were found to have IC(50) values (inhibitory activities) of 144 microM and 48 microM, compared to 0.18 microM for native conotoxin G1.

U2 - 10.1002/cbic.200390030

DO - 10.1002/cbic.200390030

M3 - Journal article

C2 - 12616632

SN - 1439-4227

VL - 4

SP - 186

EP - 194

JO - ChemBioChem

JF - ChemBioChem

IS - 2-3

ER -