Synthesis of bioengineered heparin chemically and biologically similar to porcine-derived products and convertible to low MW heparin.

Autor:	Douaisi M; Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, NY 12180., Paskaleva EE; Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, NY 12180., Fu L; Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, NY 12180., Grover N; Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, NY 12180., McManaman CL; Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, NY 12180., Varghese S; Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, NY 12180., Brodfuehrer PR; Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, NY 12180., Gibson JM; Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, NY 12180., de Joode I; Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, NY 12180., Xia K; Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, NY 12180., Brier MI; Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, NY 12180.; Department of Chemical and Biological Engineering, Rensselaer Polytechnic Institute, Troy, NY 12180., Simmons TJ; Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, NY 12180., Datta P; Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, NY 12180., Zhang F; Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, NY 12180.; Department of Chemical and Biological Engineering, Rensselaer Polytechnic Institute, Troy, NY 12180., Onishi A; Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, NY 12180., Hirakane M; Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, NY 12180., Mori D; Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, NY 12180., Linhardt RJ; Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, NY 12180.; Department of Chemical and Biological Engineering, Rensselaer Polytechnic Institute, Troy, NY 12180.; Department of Chemistry and Chemical Biology, Rensselaer Polytechnic Institute, Troy, NY 12180.; Department of Biomedical Engineering, Rensselaer Polytechnic Institute, Troy, NY 12180.; Department of Biological Sciences, Rensselaer Polytechnic Institute, Troy, NY 12180., Dordick JS; Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, NY 12180.; Department of Chemical and Biological Engineering, Rensselaer Polytechnic Institute, Troy, NY 12180.; Department of Biomedical Engineering, Rensselaer Polytechnic Institute, Troy, NY 12180.; Department of Biological Sciences, Rensselaer Polytechnic Institute, Troy, NY 12180.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2024 Apr 02; Vol. 121 (14), pp. e2315586121. Date of Electronic Publication: 2024 Mar 18.
DOI:	10.1073/pnas.2315586121
Abstrakt:	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. Competing Interests: Competing interests statement:The following authors are inventors on U.S. Patent 11,591,628, which has been licensed commercially and may benefit from royalties: M.D., E.E.P., L.F., N.G., P.R.B., T.J.S., P.D., A.O., M.H., D.M., R.J.L., and J.S.D.
Databáze:	MEDLINE
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