Heavy heparin: A stable isotope-enriched, chemoenzymatically-synthesized, poly-component drug

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Authors
Cress, Brady F.
Bhaskar, Ujjwal
Vaidyanathan, Deepika
Williams, Asher
Cai, Chao
Liu, Xinyue
Fu, Li
M-Chari, Vandhana
Zhang, Fuming
Mousa, Shaker A.
Issue Date
2019-04-23
Type
Article
Language
ENG
Keywords
Biology , Chemistry and chemical biology , Chemical and biological engineering , Biomedical engineering
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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.
Description
Angewandte Chemie, 58, 5962 –5966
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Full Citation
Heavy heparin: A stable isotope-enriched, chemoenzymatically-synthesized, poly-component drug, B. F. Cress, U. Bhaskar, D. Vaidyanathan, A. Williams, C. Cai, X. Liu, L. Fu, V. M-Chari, F. Zhang, S. A. Mousa, J. S. Dordick, M. A. G. Koffas, R. J. Linhardt, Angewandte Chemie, 58, 5962 –5966, 2019.
Publisher
Wiley
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PubMed ID
DOI
ISSN
15213773
14337851
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