Molecular size is important for the safety and selective inhibition of intrinsic factor Xase for fucosylated chondroitin sulfate

Lufeng Yan, Junhui Li, Danli Wang, Tian Ding, Yaqin Hu, Xingqian Ye, Robert J. Linhardt, Shiguo Chen

Research output: Contribution to journalArticlepeer-review

32 Scopus citations

Abstract

Fucosylated chondroitin sulfate from sea cucumber Isostichopus badionotus (FCS-Ib) showed potent anticoagulant activities without selectivity. The present study focused on developing safe FCS-Ib oligomers showing selective inhibition of intrinsic factor Xase (anti-FXase) prepared through partial N-deacetylation–deaminative cleavage. The N-deacetylation degree was regulated by reaction time, controlling the resulting oligomer distribution. Structure analysis confirmed the selectivity of degradation, and 12 high purity fractions with trisaccharide-repeating units were separated. In vitro anticoagulant assays indicated a decrease in molecular weight (Mw) dramatically reduced activated partial thromboplastin time (APTT), thrombin time (TT), AT-dependent anti-FIIa and anti-FXa activities, while the oligomers retained potent anti-FXase activity until they fell below 3 kDa. Meanwhile, human FXII activation and platelet aggregation were markedly reduced with decreasing Mw and were moderate when under 12.0 kDa. Thus, fragments of 3–12.0 kDa should be safe and effective as selective inhibitors of intrinsic tenase complex for application as clinical anticoagulants.

Original languageEnglish
Pages (from-to)180-189
Number of pages10
JournalCarbohydrate Polymers
Volume178
DOIs
StatePublished - 15 Dec 2017
Externally publishedYes

Keywords

  • Anticoagulant activity
  • Fucosylated chondroitin sulfate
  • Intrinsic tenase complex inhibitor
  • N-deacetylation–deaminative cleavage
  • Safe fragments

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