Heparin Mimetics: Their Therapeutic Potential

Abstract

Heparin mimetics are synthetic and semi-synthetic compounds that are highly sulfated, structurally distinct analogues of glycosaminoglycans. These mimetics are often rationally designed to increase potency and binding selectivity towards specific proteins involved in disease manifestations. Some of the major therapeutic arenas towards which heparin mimetics are targeted include: coagulation and thrombosis, cancers, and inflammatory diseases. Although Fondaparinux, a rationally designed heparin mimetic, is now approved for prophylaxis and treatment of venous thromboembolism, the search for novel anticoagulant heparin mimetics with increased affinity and fewer side effects remains a subject of research. However, increasingly, research is focusing on the non-anticoagulant activities of these molecules. Heparin mimetics have potential as anti-cancer agents due to their ability to: (1) inhibit heparanase, an endoglycosidase which facilitates the spread of tumor cells; and (2) inhibit angiogenesis by binding to growth factors. The heparin mimetic, PI-88 is in clinical trials for post-surgical hepatocellular carcinoma and advanced melanoma. The anti-inflammatory properties of heparin mimetics have primarily been attributed to their ability to interact with: complement system proteins, selectins and chemokines; each of which function differently to facilitate inflammation. The efficacy of low/non-anticoagulant heparin mimetics in animal models of different inflammatory diseases has been demonstrated. These findings, plus clinical data that indicates heparin has anti-inflammatory activity, will raise the momentum for developing heparin mimetics as a new class of therapeutic agent for inflammatory diseases.

Keywords: anti-inflammatory; anticoagulant; cancer; glycosaminoglycan; heparan sulfate; heparin; heparin mimetics.

Figure 1

(a) Cartoon illustration of heparin and heparan sulfate structure; (b) Major and minor disaccharide repeating units in heparin and heparan sulfate.

Figure 2

Chemical structure of heparin pentasccharide derivatives. (a) The antithrombin III binding pentasccharide motif of heparin; (b–d) Structure of synthetic analogues of the antithrombin III binding site of heparin.

Figure 3

Chemical structure of (a) 17-mer saccharide; (b) SR123781.

Figure 4

Chemical structure of tailored glycopolymers as anticoagulant heparin mimetics.

Figure 5

(a) Generalized chemical structure of PI-88; (b–d) Analogues of PI-88; (e) Chemical structure of PG545.

Figure 6

Small molecule heparin/heparan sulfate (HS) mimetics as potential inhibitors of fibroblast growth factors (FGF)-and/or vascular endothelial growth factor (VEGF) mediated angiogenesis for the development of novel cancer therapeutics; Structure of potent (a,b) linked cyclitol; (c,d) compounds from Ugi library; (e) compounds synthesized via click chemistry.

Figure 7

Schematic representation of (a) SST0001 (roneoparstat) (b) M402 (necuparanib). The actual structures may retain the microheterogeneity of the original heparin and low-molecular-weight-heparin (LMWH) [89].

Figure 8

Chemical structure of the conjugated and radiolabeled octasaccharide-based HS mimetic.

Figure 9

Chemical structure of (a) Sialyl Lewis^x (sLe^x); (b) GM-1070, sLe^x mimic in clinical trials for treatment of vaso-occlusive crisis in sickle cell disease patients; (c) sLe^x mimic that maximizes conformational pre-organization of the binding determinants; (d) sLe^x mimic designed using fragment based discovery techniques with improved binding kinetics.

Figure 10

Structure of PS3; the sodium salt of a β-1,3-glucan sulfate with a degree of sulfation of 2.2 and a polydispersity of 25 corresponding to a mean molecular weight of 10,000.

Figure 11

Structure of dendritic polyglycerol heparin mimetics: The structure of dendritic polyglycerols (dPG) scaffold illustrates an idealized fragment of the polymer. (A) Structure of (a) dendritic polyglycerol starting material and (b) dendritic polyglycerol heparin mimetics synthesized via click coupling by Weinhart et al. [117]; (B) Structure of (c) dendritic polyglycerol starting material and (d,e) radiolabeled dendritic polyglycerol heparin mimetics synthesized by Pant et al. [118]; (C) Structure of (f) dendritic polyglycerol starting material and (g–i) shell cleavable dendritic polyglycerol heparin mimetics synthesized by Reimann et al. [95].

Figure 12

Site-specifically 6-O-sulfated dodecasaccharides: (a) completely non-6-O-sulfated (b) site-selectively mono-6-O-sulfated (c) fully 6-O-sulfated.

Figure 13

The unnatural synthetic monosaccharide, Di-S-IdoA containing two axial sulfate groups.

Figure 14

(a) Heparin tetrasaccharide which possess the minimal chain length for anti-allergic and anti-inflammatory properties (b) Supersulfated heparin derived disaccharide, Hep-SSD.

Figure 15

Structure and degree of sulfation of N-arylacyl O-sulfonated aminoglycosides (a) Kanamycin core derivatives (b) Neomycin core derivatives.