Heparin mimetics with anticoagulant activity

Abstract

Heparin, a sulfated polysaccharide belonging to the glycosaminoglycan family, has been widely used as an anticoagulant drug for decades and remains the most commonly used parenteral anticoagulant in adults and children. However, heparin has important clinical limitations and is derived from animal sources which pose significant safety and supply problems. The ever growing shortage of the raw material for heparin manufacturing may become a very significant issue in the future. These global limitations have prompted much research, especially following the recent well-publicized contamination scandal, into the development of alternative anticoagulants derived from non-animal and/or totally synthetic sources that mimic the structural features and properties of heparin. Such compounds, termed heparin mimetics, are also needed as anticoagulant materials for use in biomedical applications (e.g., stents, grafts, implants etc.). This review encompasses the development of heparin mimetics of various structural classes, including synthetic polymers and non-carbohydrate small molecules as well as sulfated oligo- and polysaccharides, and fondaparinux derivatives and conjugates, with a focus on developments in the past 10 years.

Sulfonated RAFT Copolymers as Heparin Mimetics: Synthesis, Reactivity Ratios, and Anticoagulant Activity

“…There was a clear trend of increasing potency with increasing molecular weight, as seen in previous studies. [10,25] The data are thus presented in Figure 3A,C for 1:1 copolymers of MW 20 kDa, and in Figures S13-S18 and Tables S15-S17, Supporting Information for 1:1 copolymers of different MW and those with different monomer ratios. Unfractionated heparin (UFH) was used as the standard over the range of 1.0 -150.0 µg mL −1 , equivalent to 0.1-15.0 IU mL −1 .…”

“…Increased anticoagulant activity was generally correlated with increased molecular weight, a general trend seen in previous studies of heparin mimetics. [10] However, it is clear that there were some intriguing structure-activity relationships beyond molecular weight. Variations in monomer composition (and distribution) resulted in copolymers with different affinities for their target proteins, as reflected in some interesting and subtle changes in anticoagulant activity.…”

“…as alternatives to heparin both as anticoagulants [10][11][12][13][14] or for other therapeutic uses. [15] In addition, there has been significant interest in the development of mimetics of the related GAG heparan sulfate, [16] particularly for biological applications where anticoagulant activity is an undesired side effect, for example, for use in stabilizing or activating growth factors such as FGF and VEGF, [17][18][19][20][21][22][23] or the promotion of stem cell differentiation.…”

Anti-Thrombin, Anti-Adhesive, Anti-Migratory, and Anti-Proliferative Activities of Sulfated Galactans from the Tropical Green Seaweed, Udotea flabellum

“…In addition, it inhibits tumorigenic actions induced by IIa and FXa, conferring a survival benefit in cancer patients and the regression of primary tumors [9]. However, the use of heparin can cause side effects such as the development of thrombocytopenia, arterial embolism, bleeding complications, and even death of the patient [10]. In addition, the problem of heparin deliberate contamination with super sulfated chondroitin can induce death of the patient [11].…”

GlycoTorch Vina: Improved Docking of Sulfated Sugars Using QM-derived Scoring Functions

“…20 Biological heparin, a high molecular weight polysaccharide, has a long history of use as a clinical anticoagulant, which continues to this day. [21][22] Through over a decade of research, a pentasaccharide representing the minimum active heparin sequence was characterized, and later a synthetic version was commercialized as the low molecular weight anticoagulant, fondaparinux (See Figure 1b). 23 Importantly, it was shown that sulfated IdoA was required for binding to AT.…”