24 ヒト複合型シアリル糖鎖をもつ糖タンパク質の化学合成(口頭発表の部)

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概要

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• Oligosaccharide chains on the protein play important roles for several biological events as a posttranslational modification, therefore synthesis of glycoprotein and glycopeptide having intact and homogeneous oligosaccharide chains have been paid an attention. In order to investigate function of oligosaccharide on protein, we have examined to establish synthetic method of glycopeptide having homogeneous oligosaccharide and then to synthesize glycoprotein. For the synthesis of protein, native chemical ligation has been used as a powerful coupling method of two peptide fragments. The ligation occurs between the C-terminal thioester in the peptide and Cysteine at the N-terminal of another peptide to afford native amide bond formation. A convenient synthetic method of glycopeptide-thioester is, therefore, essential for the synthesis of glycoprotein by native chemical ligation. Although several preparation methods of peptide-thioester have been reported, a convenient preparation method of sialylglycopeptide-thioester has not been established yet. We have examined to establish a concise synthetic method of glycopeptide thioester having intact complex type dibranched disialyloligosaccharide. The synthetic strategy employs a coupling reaction between benzylthiol and free carboxylic acid at the C-terminal of glycopeptide in which peptide side chain are protected. After construction of glycopeptide on the HMPB-PEGA resin through Fmoc-strategy, protected glycopeptide was released by use of acetic acid/trifluoroethanol. Then we examined a coupling reaction between C-terminal carboxylic acid and benzylthiol under -20 degree in DMF by use of PyBOP/DIPEA. This condition is the best to form thioester and to avoid racemization. Finally, protecting groups of glycopeptide-thioester were removed by 95 TFA to afford glycopeptide-thioester having intact and homogeneous complex type disialyloligosaccharide in good yields. In addition, we have examined the synthesis of glycoprotein, Chemokine (MCP-3) by use of this technique. These glycoprotein consists of 76 amino acids and have asparagines linked oligosaccharide. Our synthetic strategy for glycoproteins uses coupling of peptide-segment strategy and then these will be coupled by repetitive native chemical ligation. This strategy afforded desired glycoprotein having a homogeneous oligosaccharide first time.

• 2006-09-15

著者

• 梶原 康宏

  横浜市立大学大学院国際総合科学研究科

• 平野 桐子

  横浜市立大学・院

• 山本 直毅

  横浜市立大学院

• 吉原 章子

  横浜市立大学院

• Dawson P.

  スクリップス研究所

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