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Angew Chem Int Ed Engl. 2019 Apr 23;58(18):5962-5966. doi: 10.1002/anie.201900768. Epub 2019 Apr 1.

Heavy Heparin: A Stable Isotope-Enriched, Chemoenzymatically-Synthesized, Poly-Component Drug.

Author information

1
CBIS, RPI, 110 8th St., Troy, NY, 12180, USA.
2
Department of Chemical and Biological Engineering, RPI, 110 8th St., Troy, NY, 12180, USA.
3
Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, 106 New Scotland Ave., Albany, NY, 12208, USA.
4
PRI, Albany College of Pharmacy and Health Sciences, 106 New Scotland Ave., Albany, NY, 12208, USA.
5
Department of Biological Sciences, RPI, 110 8th St., Troy, NY, 12180, USA.
6
Department of Chemistry and Chemical Biology, RPI, 110 8th St., Troy, NY, 12180, USA.

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.

KEYWORDS:

chemoenzymatic synthesis; deuterated drugs; heparin; pharmacology; stable isotope labeling

PMID:
30870573
PMCID:
PMC6461503
[Available on 2020-04-23]
DOI:
10.1002/anie.201900768

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