title: Homogeneous low-molecular-weight heparins with reversible anticoagulant activity.
abstract: Low-molecular-weight heparins (LMWHs) are carbohydrate-based anticoagulants clinically used to treat thrombotic disorders, but impurities, structural heterogeneity or functional irreversibility can limit treatment options. We report a series of synthetic LMWHs prepared by cost-effective chemoenzymatic methods. The high activity of one defined synthetic LMWH against human factor Xa (FXa) was reversible in vitro and in vivo using protamine, demonstrating that synthetically accessible constructs can have a critical role in the next generation of LMWHs.
authors.affiliation: Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina, USA.
authors.forename: Yongmei
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Department of Chemistry and Chemical Biology, Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, New York, USA.
authors.forename: Chao
authors.initials: C
authors.lastname: Cai
authors.affiliation: Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina, USA.
authors.forename: Kasemsiri
authors.initials: K
authors.lastname: Chandarajoti
authors.affiliation: Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina, USA.
authors.forename: Po-Hung
authors.initials: PH
authors.lastname: Hsieh
authors.affiliation: Department of Chemistry and Chemical Biology, Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, New York, USA.
authors.forename: Lingyun
authors.initials: L
authors.lastname: Li
authors.affiliation: Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina, USA.
authors.forename: Truong Q
authors.initials: TQ
authors.lastname: Pham
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, McAllister Heart Institute, University of North Carolina, Chapel Hill, North Carolina, USA.
authors.forename: Erica M
authors.initials: EM
authors.lastname: Sparkenbaugh
authors.affiliation: Institute of Biochemical and Biotechnological Drug, School of Pharmaceutical Science, Shandong University, Jinan, China.
authors.forename: Juzheng
authors.initials: J
authors.lastname: Sheng
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, McAllister Heart Institute, University of North Carolina, Chapel Hill, North Carolina, USA.
authors.forename: Nigel S
authors.initials: NS
authors.lastname: Key
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, McAllister Heart Institute, University of North Carolina, Chapel Hill, North Carolina, USA.
authors.forename: Rafal
authors.initials: R
authors.lastname: Pawlinski
authors.affiliation: Department of Biochemistry, University of Nebraska, Lincoln, Nebraska, USA.
authors.forename: Edward N
authors.initials: EN
authors.lastname: Harris
authors.affiliation: Department of Chemistry and Chemical Biology, Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, New York, USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Linhardt
authors.affiliation: Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Liu
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000037:antagonists & inhibitors* / Q000138:chemical synthesis* / Q000494:pharmacology; D000991:Antithrombins / Q000378:metabolism / Q000494:pharmacology; D002240:Carbohydrate Sequence; D015816:Cell Adhesion Molecules, Neuronal / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D065427:Factor Xa Inhibitors; D006470:Hemorrhage / Q000188:drug therapy; D006495:Heparin, Low-Molecular-Weight / Q000037:antagonists & inhibitors* / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D007202:Indicators and Reagents; D007553:Isotope Labeling; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D011479:Protamines / Q000494:pharmacology; D021241:Spectrometry, Mass, Electrospray Ionization; D013462:Sulfur Radioisotopes
chemical_list: D000925:Anticoagulants; D000991:Antithrombins; D015816:Cell Adhesion Molecules, Neuronal; D065427:Factor Xa Inhibitors; D006495:Heparin, Low-Molecular-Weight; D007202:Indicators and Reagents; D011479:Protamines; C486733:Stab2 protein, mouse; D013462:Sulfur Radioisotopes