Heavy Heparin: A Stable Isotope‐Enriched, Chemoenzymatically‐Synthesized, Poly‐Component Drug. (1st April 2019)

• Record Type: Journal Article
• Authors: Cress, Brady F.; Bhaskar, Ujjwal; Vaidyanathan, Deepika; Williams, Asher; Cai, Chao; Liu, Xinyue; Fu, Li; M‐Chari, Vandhana; Zhang, Fuming; Mousa, Shaker A.; Dordick, Jonathan S.; Koffas, Mattheos A. G.; Linhardt, Robert J.
• Is Part Of: Angewandte Chemie. Volume 131:Number 18(2019)
• Page Start: 6023
• Page End: 6027
• Publication Date: 2019-04-01
• Subjects: Chemoenzymatische Synthese -- Deuterierte Wirkstoffe -- Heparin -- Pharmakologie -- Stabile Isotopenmarkierung; Chemistry -- Periodicals; 540
• DOI: 10.1002/ange.201900768
• Languages: English
• ISSNs: 0044-8249

Abstract

Abstract: Heparin is a highly sulfated, complex polysaccharide and widely used anticoagulant pharmaceutical. In this work, we chemoenzymatically synthesized perdeuteroheparin from biosynthetically enriched heparosan precursor obtained from microbial culture in deuterated medium. Chemical de‐ N ‐acetylation, chemical N ‐sulfation, enzymatic epimerization, and enzymatic sulfation with recombinant heparin biosynthetic enzymes afforded perdeuteroheparin comparable to pharmaceutical heparin. A series of applications for heavy heparin and its heavy biosynthetic intermediates are demonstrated, including generation of stable isotope labeled disaccharide standards, development of a non‐radioactive NMR assay for glucuronosyl‐C5‐epimerase, and background‐free quantification of in vivo half‐life following administration to rabbits. We anticipate that this approach can be extended to produce other isotope‐enriched glycosaminoglycans.