title: The design and synthesis of new synthetic low-molecular-weight heparins.
abstract: Low-molecular-weight heparin (LMWH) has remained the most favorable form of heparin in clinics since the 1990s owing to its predictable pharmacokinetic properties. However, LMWH is mainly eliminated through the kidney, which limits its use in renal-impaired patients. In addition, the anticoagulant activity of LMWH is only partially neutralized by protamine. LMWH is obtained from a full-length, highly sulfated polysaccharide harvested from porcine mucosal tissue. The depolymerization involved in LMWH production generates a broad distribution of LMWH fragments (6-22 sugar residues). This, combined with the various methods used to produce commercial LMWHs, results in variable pharmacological and pharmacokinetic properties. An alternative chemoenzymatic approach offers a method for the synthesis of LMWH that has the potential to overcome the limitations of current LMWHs. This review summarizes the application of a chemoenzymatic approach to generate LMWH and the rationale for development of a synthetic LMWH.
authors.affiliation: Division of Hematology and Oncology, McAllister Heart Institute, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.|Department of Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences, Prince of Songkla University, Hat Yai, Songkhla, Thailand.
authors.forename: K
authors.initials: K
authors.lastname: Chandarajoti
authors.affiliation: Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: J
authors.initials: J
authors.lastname: Liu
authors.affiliation: Division of Hematology and Oncology, McAllister Heart Institute, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: R
authors.initials: R
authors.lastname: Pawlinski
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000138:chemical synthesis* / Q000494:pharmacology; D001777:Blood Coagulation / Q000187:drug effects; D002241:Carbohydrates / Q000737:chemistry; D015195:Drug Design; D006495:Heparin, Low-Molecular-Weight / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D007668:Kidney / Q000187:drug effects; D051379:Mice; D008970:Molecular Weight; D009092:Mucous Membrane / Q000378:metabolism; D058105:Polymerization; D011134:Polysaccharides / Q000737:chemistry; D011479:Protamines / Q000737:chemistry; D011485:Protein Binding; D013552:Swine
chemical_list: D000925:Anticoagulants; D002241:Carbohydrates; D006495:Heparin, Low-Molecular-Weight; D011134:Polysaccharides; D011479:Protamines
keywords: anticoagulants; enzymes; heparin; low molecular weight; protamines; synthetic