Synthetic oligosaccharides can replace animal-sourced low-molecular weight heparins.
Identifieur interne : 000B68 ( Main/Exploration ); précédent : 000B67; suivant : 000B69Synthetic oligosaccharides can replace animal-sourced low-molecular weight heparins.
Auteurs : Yongmei Xu [États-Unis] ; Kasemsiri Chandarajoti [États-Unis] ; Xing Zhang [États-Unis] ; Vijayakanth Pagadala [États-Unis] ; Wenfang Dou [États-Unis] ; Debra Moorman Hoppensteadt [États-Unis] ; Erica M. Sparkenbaugh [États-Unis] ; Brian Cooley [États-Unis] ; Sharon Daily [États-Unis] ; Nigel S. Key [États-Unis] ; Diana Severynse-Stevens [États-Unis] ; Jawed Fareed [États-Unis] ; Robert J. Linhardt [États-Unis] ; Rafal Pawlinski [États-Unis] ; Jian Liu [États-Unis]Source :
- Science translational medicine [ 1946-6242 ] ; 2017.
Descripteurs français
- KwdFr :
- MESH :
- anatomopathologie : Lésion d'ischémie-reperfusion, Rein.
- pharmacologie : Anticoagulants, Héparine bas poids moléculaire, Oligosaccharides.
- Animaux, Modèles animaux de maladie humaine, Primates, Taille d'organe.
English descriptors
- KwdEn :
- MESH :
- chemical , pharmacology : Anticoagulants, Heparin, Low-Molecular-Weight, Oligosaccharides.
- drug effects : Organ Size.
- pathology : Kidney, Reperfusion Injury.
- Animals, Disease Models, Animal, Primates.
Abstract
Low-molecular weight heparin (LMWH) is used clinically to treat clotting disorders. As an animal-sourced product, LMWH is a highly heterogeneous mixture, and its anticoagulant activity is not fully reversible by protamine. Furthermore, the reliability of the LMWH supply chain is a concern for regulatory agencies. We demonstrate the synthesis of heparin dodecasaccharides (12-mers) at the gram scale. In vitro experiments demonstrate that the anticoagulant activity of the 12-mers could be reversed using protamine. One of these, labeled as 12-mer-1, reduced the size of blood clots in the mouse model of deep vein thrombosis and attenuated circulating procoagulant markers in the mouse model of sickle cell disease. An ex vivo experiment demonstrates that the anticoagulant activity of 12-mer-1 could be reversed by protamine. 12-mer-1 was also examined in a nonhuman primate model to determine its pharmacodynamic parameters. A 7-day toxicity study in a rat model showed no toxic effects. The data suggest that a synthetic homogeneous oligosaccharide can replace animal-sourced LMWHs.
DOI: 10.1126/scitranslmed.aan5954
PubMed: 28878012
Affiliations:
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type="wicri:Area/Main/Exploration">000B68</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">Synthetic oligosaccharides can replace animal-sourced low-molecular weight heparins.</title><author><name sortKey="Xu, Yongmei" sort="Xu, Yongmei" uniqKey="Xu Y" first="Yongmei" last="Xu">Yongmei Xu</name><affiliation wicri:level="2"><nlm:affiliation>Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599</wicri:regionArea><placeName><region type="state">Caroline du Nord</region></placeName></affiliation></author><author><name sortKey="Chandarajoti, Kasemsiri" sort="Chandarajoti, Kasemsiri" uniqKey="Chandarajoti K" first="Kasemsiri" last="Chandarajoti">Kasemsiri Chandarajoti</name><affiliation wicri:level="2"><nlm:affiliation>Division of Hematology/Oncology, Department of Medicine, University of North Carolina, Chapel Hill, NC 27599, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Division of Hematology/Oncology, Department of Medicine, University of North Carolina, Chapel Hill, NC 27599</wicri:regionArea><placeName><region type="state">Caroline du Nord</region></placeName></affiliation></author><author><name sortKey="Zhang, Xing" sort="Zhang, Xing" uniqKey="Zhang X" first="Xing" last="Zhang">Xing Zhang</name><affiliation wicri:level="2"><nlm:affiliation>Department of Chemistry and Chemical Biology, Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, NY 12180, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Chemistry and Chemical Biology, Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, NY 12180</wicri:regionArea><placeName><region type="state">État de New York</region></placeName></affiliation></author><author><name sortKey="Pagadala, Vijayakanth" sort="Pagadala, Vijayakanth" uniqKey="Pagadala V" first="Vijayakanth" last="Pagadala">Vijayakanth Pagadala</name><affiliation wicri:level="2"><nlm:affiliation>Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599</wicri:regionArea><placeName><region type="state">Caroline du Nord</region></placeName></affiliation></author><author><name sortKey="Dou, Wenfang" sort="Dou, Wenfang" uniqKey="Dou W" first="Wenfang" last="Dou">Wenfang Dou</name><affiliation wicri:level="2"><nlm:affiliation>Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599</wicri:regionArea><placeName><region type="state">Caroline du Nord</region></placeName></affiliation></author><author><name sortKey="Hoppensteadt, Debra Moorman" sort="Hoppensteadt, Debra Moorman" uniqKey="Hoppensteadt D" first="Debra Moorman" last="Hoppensteadt">Debra Moorman Hoppensteadt</name><affiliation wicri:level="2"><nlm:affiliation>Department of Pathology, Loyola University Medical Center, Maywood, IL 60660, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Pathology, Loyola University Medical Center, Maywood, IL 60660</wicri:regionArea><placeName><region type="state">Illinois</region></placeName></affiliation></author><author><name sortKey="Sparkenbaugh, Erica M" sort="Sparkenbaugh, Erica M" uniqKey="Sparkenbaugh E" first="Erica M" last="Sparkenbaugh">Erica M. Sparkenbaugh</name><affiliation wicri:level="2"><nlm:affiliation>Division of Hematology/Oncology, Department of Medicine, University of North Carolina, Chapel Hill, NC 27599, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Division of Hematology/Oncology, Department of Medicine, University of North Carolina, Chapel Hill, NC 27599</wicri:regionArea><placeName><region type="state">Caroline du Nord</region></placeName></affiliation></author><author><name sortKey="Cooley, Brian" sort="Cooley, Brian" uniqKey="Cooley B" first="Brian" last="Cooley">Brian Cooley</name><affiliation wicri:level="2"><nlm:affiliation>Department of Pathology and Laboratory Medicine, School of Medicine, University of North Carolina, Chapel Hill, NC 27599, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Pathology and Laboratory Medicine, School of Medicine, University of North Carolina, Chapel Hill, NC 27599</wicri:regionArea><placeName><region type="state">Caroline du Nord</region></placeName></affiliation></author><author><name sortKey="Daily, Sharon" sort="Daily, Sharon" uniqKey="Daily S" first="Sharon" last="Daily">Sharon Daily</name><affiliation wicri:level="2"><nlm:affiliation>Center for Global Health, RTI International, Research Triangle Park, NC 27709, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Center for Global Health, RTI International, Research Triangle Park, NC 27709</wicri:regionArea><placeName><region type="state">Caroline du Nord</region></placeName></affiliation></author><author><name sortKey="Key, Nigel S" sort="Key, Nigel S" uniqKey="Key N" first="Nigel S" last="Key">Nigel S. Key</name><affiliation wicri:level="2"><nlm:affiliation>Division of Hematology/Oncology, Department of Medicine, University of North Carolina, Chapel Hill, NC 27599, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Division of Hematology/Oncology, Department of Medicine, University of North Carolina, Chapel Hill, NC 27599</wicri:regionArea><placeName><region type="state">Caroline du Nord</region></placeName></affiliation></author><author><name sortKey="Severynse Stevens, Diana" sort="Severynse Stevens, Diana" uniqKey="Severynse Stevens D" first="Diana" last="Severynse-Stevens">Diana Severynse-Stevens</name><affiliation wicri:level="2"><nlm:affiliation>Center for Global Health, RTI International, Research Triangle Park, NC 27709, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Center for Global Health, RTI International, Research Triangle Park, NC 27709</wicri:regionArea><placeName><region type="state">Caroline du Nord</region></placeName></affiliation></author><author><name sortKey="Fareed, Jawed" sort="Fareed, Jawed" uniqKey="Fareed J" first="Jawed" last="Fareed">Jawed Fareed</name><affiliation wicri:level="2"><nlm:affiliation>Department of Pathology, Loyola University Medical Center, Maywood, IL 60660, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Pathology, Loyola University Medical Center, Maywood, IL 60660</wicri:regionArea><placeName><region type="state">Illinois</region></placeName></affiliation></author><author><name sortKey="Linhardt, Robert J" sort="Linhardt, Robert J" uniqKey="Linhardt R" first="Robert J" last="Linhardt">Robert J. Linhardt</name><affiliation wicri:level="2"><nlm:affiliation>Department of Chemistry and Chemical Biology, Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, NY 12180, USA. jian_liu@unc.edu rafal_pawlinski@med.unc.edu linhar@rpi.edu.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Chemistry and Chemical Biology, Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, NY 12180</wicri:regionArea><placeName><region type="state">État de New York</region></placeName></affiliation></author><author><name sortKey="Pawlinski, Rafal" sort="Pawlinski, Rafal" uniqKey="Pawlinski R" first="Rafal" last="Pawlinski">Rafal Pawlinski</name><affiliation wicri:level="2"><nlm:affiliation>Division of Hematology/Oncology, Department of Medicine, University of North Carolina, Chapel Hill, NC 27599, USA. jian_liu@unc.edu rafal_pawlinski@med.unc.edu linhar@rpi.edu.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Division of Hematology/Oncology, Department of Medicine, University of North Carolina, Chapel Hill, NC 27599</wicri:regionArea><placeName><region type="state">Caroline du Nord</region></placeName></affiliation></author><author><name sortKey="Liu, Jian" sort="Liu, Jian" uniqKey="Liu J" first="Jian" last="Liu">Jian Liu</name><affiliation wicri:level="2"><nlm:affiliation>Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, USA. jian_liu@unc.edu rafal_pawlinski@med.unc.edu linhar@rpi.edu.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599</wicri:regionArea><placeName><region type="state">Caroline du Nord</region></placeName></affiliation></author></analytic><series><title level="j">Science translational medicine</title><idno type="eISSN">1946-6242</idno><imprint><date when="2017" type="published">2017</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animals</term><term>Anticoagulants (pharmacology)</term><term>Disease Models, Animal</term><term>Heparin, Low-Molecular-Weight (pharmacology)</term><term>Kidney (pathology)</term><term>Oligosaccharides (pharmacology)</term><term>Organ Size (drug effects)</term><term>Primates</term><term>Reperfusion Injury (pathology)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Animaux</term><term>Anticoagulants (pharmacologie)</term><term>Héparine bas poids moléculaire (pharmacologie)</term><term>Lésion d'ischémie-reperfusion (anatomopathologie)</term><term>Modèles animaux de maladie humaine</term><term>Oligosaccharides (pharmacologie)</term><term>Primates</term><term>Rein (anatomopathologie)</term><term>Taille d'organe ()</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Anticoagulants</term><term>Heparin, Low-Molecular-Weight</term><term>Oligosaccharides</term></keywords><keywords scheme="MESH" qualifier="anatomopathologie" xml:lang="fr"><term>Lésion d'ischémie-reperfusion</term><term>Rein</term></keywords><keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Organ Size</term></keywords><keywords scheme="MESH" qualifier="pathology" xml:lang="en"><term>Kidney</term><term>Reperfusion Injury</term></keywords><keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Anticoagulants</term><term>Héparine bas poids moléculaire</term><term>Oligosaccharides</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>Disease Models, Animal</term><term>Primates</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Animaux</term><term>Modèles animaux de maladie humaine</term><term>Primates</term><term>Taille d'organe</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Low-molecular weight heparin (LMWH) is used clinically to treat clotting disorders. As an animal-sourced product, LMWH is a highly heterogeneous mixture, and its anticoagulant activity is not fully reversible by protamine. Furthermore, the reliability of the LMWH supply chain is a concern for regulatory agencies. We demonstrate the synthesis of heparin dodecasaccharides (12-mers) at the gram scale. In vitro experiments demonstrate that the anticoagulant activity of the 12-mers could be reversed using protamine. One of these, labeled as 12-mer-1, reduced the size of blood clots in the mouse model of deep vein thrombosis and attenuated circulating procoagulant markers in the mouse model of sickle cell disease. An ex vivo experiment demonstrates that the anticoagulant activity of 12-mer-1 could be reversed by protamine. 12-mer-1 was also examined in a nonhuman primate model to determine its pharmacodynamic parameters. A 7-day toxicity study in a rat model showed no toxic effects. The data suggest that a synthetic homogeneous oligosaccharide can replace animal-sourced LMWHs.</div></front></TEI><affiliations><list><country><li>États-Unis</li></country><region><li>Caroline du Nord</li><li>Illinois</li><li>État de New York</li></region></list><tree><country name="États-Unis"><region name="Caroline du Nord"><name sortKey="Xu, Yongmei" sort="Xu, Yongmei" uniqKey="Xu Y" first="Yongmei" last="Xu">Yongmei Xu</name></region><name sortKey="Chandarajoti, Kasemsiri" sort="Chandarajoti, Kasemsiri" uniqKey="Chandarajoti K" first="Kasemsiri" last="Chandarajoti">Kasemsiri Chandarajoti</name><name sortKey="Cooley, Brian" sort="Cooley, Brian" uniqKey="Cooley B" first="Brian" last="Cooley">Brian Cooley</name><name sortKey="Daily, Sharon" sort="Daily, Sharon" uniqKey="Daily S" first="Sharon" last="Daily">Sharon Daily</name><name sortKey="Dou, Wenfang" sort="Dou, Wenfang" uniqKey="Dou W" first="Wenfang" last="Dou">Wenfang Dou</name><name sortKey="Fareed, Jawed" sort="Fareed, Jawed" uniqKey="Fareed J" first="Jawed" last="Fareed">Jawed Fareed</name><name sortKey="Hoppensteadt, Debra Moorman" sort="Hoppensteadt, Debra Moorman" uniqKey="Hoppensteadt D" first="Debra Moorman" last="Hoppensteadt">Debra Moorman Hoppensteadt</name><name sortKey="Key, Nigel S" sort="Key, Nigel S" uniqKey="Key N" first="Nigel S" last="Key">Nigel S. Key</name><name sortKey="Linhardt, Robert J" sort="Linhardt, Robert J" uniqKey="Linhardt R" first="Robert J" last="Linhardt">Robert J. Linhardt</name><name sortKey="Liu, Jian" sort="Liu, Jian" uniqKey="Liu J" first="Jian" last="Liu">Jian Liu</name><name sortKey="Pagadala, Vijayakanth" sort="Pagadala, Vijayakanth" uniqKey="Pagadala V" first="Vijayakanth" last="Pagadala">Vijayakanth Pagadala</name><name sortKey="Pawlinski, Rafal" sort="Pawlinski, Rafal" uniqKey="Pawlinski R" first="Rafal" last="Pawlinski">Rafal Pawlinski</name><name sortKey="Severynse Stevens, Diana" sort="Severynse Stevens, Diana" uniqKey="Severynse Stevens D" first="Diana" last="Severynse-Stevens">Diana Severynse-Stevens</name><name sortKey="Sparkenbaugh, Erica M" sort="Sparkenbaugh, Erica M" uniqKey="Sparkenbaugh E" first="Erica M" last="Sparkenbaugh">Erica M. Sparkenbaugh</name><name sortKey="Zhang, Xing" sort="Zhang, Xing" uniqKey="Zhang X" first="Xing" last="Zhang">Xing Zhang</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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