Synthesis of bioengineered heparin chemically and biologically similar to porcine-derived products and convertible to low MW heparin
Heparins have been invaluable therapeutic anticoagulant polysaccharides for over a century, whether used as unfractionated heparin or as low molecular weight heparin (LMWH) derivatives. However, heparin production by extraction from animal tissues presents multiple challenges, including the risk of adulteration, contamination, prion and viral impurities, limited supply, insecure supply chain, and significant batch-to-batch variability. The use of animal-derived heparin also raises ethical and religious concerns, as well as carries the risk of transmitting zoonotic diseases. Chemoenzymatic synthesis of animal-free heparin products would offer several advantages, including reliable and scalable production processes, improved purity and consistency, and the ability to produce heparin polysaccharides with molecular weight, structural, and functional properties equivalent to those of the United States Pharmacopeia (USP) heparin, currently only sourced from porcine intestinal mucosa. We report a scalable process for the production of bioengineered heparin that is biologically and compositionally similar to USP heparin. This process relies on enzymes from the heparin biosynthetic pathway, immobilized on an inert support and requires a tailored N-sulfoheparosan with N-sulfo levels similar to those of porcine heparins. We also report the conversion of our bioengineered heparin into a LMWH that is biologically and compositionally similar to USP enoxaparin. Ultimately, we demonstrate major advances to a process to provide a potential clinical and sustainable alternative to porcine-derived heparin products.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:121 |
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| Enthalten in: |
Proceedings of the National Academy of Sciences of the United States of America - 121(2024), 14 vom: 02. Apr., Seite e2315586121 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Douaisi, Marc [VerfasserIn] |
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| Links: |
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| Themen: |
9005-49-6 |
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| Anmerkungen: |
Date Completed 20.03.2024 Date Revised 08.04.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1073/pnas.2315586121 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM369883721 |
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| 520 | |a Heparins have been invaluable therapeutic anticoagulant polysaccharides for over a century, whether used as unfractionated heparin or as low molecular weight heparin (LMWH) derivatives. However, heparin production by extraction from animal tissues presents multiple challenges, including the risk of adulteration, contamination, prion and viral impurities, limited supply, insecure supply chain, and significant batch-to-batch variability. The use of animal-derived heparin also raises ethical and religious concerns, as well as carries the risk of transmitting zoonotic diseases. Chemoenzymatic synthesis of animal-free heparin products would offer several advantages, including reliable and scalable production processes, improved purity and consistency, and the ability to produce heparin polysaccharides with molecular weight, structural, and functional properties equivalent to those of the United States Pharmacopeia (USP) heparin, currently only sourced from porcine intestinal mucosa. We report a scalable process for the production of bioengineered heparin that is biologically and compositionally similar to USP heparin. This process relies on enzymes from the heparin biosynthetic pathway, immobilized on an inert support and requires a tailored N-sulfoheparosan with N-sulfo levels similar to those of porcine heparins. We also report the conversion of our bioengineered heparin into a LMWH that is biologically and compositionally similar to USP enoxaparin. Ultimately, we demonstrate major advances to a process to provide a potential clinical and sustainable alternative to porcine-derived heparin products | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a USP-heparin | |
| 650 | 4 | |a bioengineered heparin | |
| 650 | 4 | |a chemoenzymatic process | |
| 650 | 4 | |a enoxaparin | |
| 650 | 4 | |a low molecular weight heparin | |
| 650 | 7 | |a Heparin |2 NLM | |
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| 700 | 1 | |a Paskaleva, Elena E |e verfasserin |4 aut | |
| 700 | 1 | |a Fu, Li |e verfasserin |4 aut | |
| 700 | 1 | |a Grover, Navdeep |e verfasserin |4 aut | |
| 700 | 1 | |a McManaman, Charity L |e verfasserin |4 aut | |
| 700 | 1 | |a Varghese, Sony |e verfasserin |4 aut | |
| 700 | 1 | |a Brodfuehrer, Paul R |e verfasserin |4 aut | |
| 700 | 1 | |a Gibson, James M |e verfasserin |4 aut | |
| 700 | 1 | |a de Joode, Ian |e verfasserin |4 aut | |
| 700 | 1 | |a Xia, Ke |e verfasserin |4 aut | |
| 700 | 1 | |a Brier, Matthew I |e verfasserin |4 aut | |
| 700 | 1 | |a Simmons, Trevor J |e verfasserin |4 aut | |
| 700 | 1 | |a Datta, Payel |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Fuming |e verfasserin |4 aut | |
| 700 | 1 | |a Onishi, Akihiro |e verfasserin |4 aut | |
| 700 | 1 | |a Hirakane, Makoto |e verfasserin |4 aut | |
| 700 | 1 | |a Mori, Daisuke |e verfasserin |4 aut | |
| 700 | 1 | |a Linhardt, Robert J |e verfasserin |4 aut | |
| 700 | 1 | |a Dordick, Jonathan S |e verfasserin |4 aut | |
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