Total synthesis of homogeneous variants of hirudin P6: A post-translationally modified anti-thrombotic leech-derived protein

Yves S.Y. Hsieh, Lakshmi C. Wijeyewickrema, Brendan L. Wilkinson, Robert N. Pike, Richard J. Payne

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

Hirudin P6 is a leech-derived anti-thrombotic protein which possesses two post-translational modifications, O-glycosylation and tyrosine sulfation. In this study we report the ligation-based synthesis of a library of hirudin P6 proteins possessing homogeneous glycosylation and sulfation modifications. The nature of the modifications incorporated was shown to have a drastic effect on inhibition against both the fibrinogenolytic and amidolytic activities of thrombin and thus highlights a potential means for attenuating the biological activity of the protein. Modifications matter: Hirudin P6 is a leech-derived anti-thrombotic protein that is natively O-glycosylated and sulfated on tyrosine. Ligation chemistry was employed to assemble a library of homogeneously modified hirudin P6 proteins with variation in glycosylation at Thr-43 and sulfation at Tyr-61. The type of post-translational modification present was shown to have a dramatic effect on inhibitory activity against both the fibrinogenolytic and amidolytic activities of thrombin.

Original languageEnglish
Pages (from-to)3947-3951
Number of pages5
JournalAngewandte Chemie - International Edition
Volume53
Issue number15
DOIs
Publication statusPublished - Apr 7 2014
Externally publishedYes

Keywords

  • glycoprotein
  • glycosylation
  • ligation
  • sulfation
  • sulfoprotein

ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)

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