Advances in the preparation and synthesis of heparin and related products

Abstract

Heparin is a naturally occurring glycosaminoglycan from livestock, principally porcine intestine, and is clinically used as an anticoagulant drug. A limitation to heparin production is that it depends on a single animal species and potential problems have been associated with animal-derived heparin. The contamination crisis in 2008 led to a search for new animal sources and the investigation of non-animal sources of heparin. Over the past 5 years, new animal sources, chemical, and chemoenzymatic methods have been introduced to prepare heparin-based drugs. In this review, we describe advances in the preparation and synthesis of heparin and related products.

Keywords: Bioengineered heparin.; Chemoenzymatic synthesis; Heparin; LMWH; Synthetic heparin.

Figure 1.

Structure of heparin derived from porcine intestine and chemically synthesized ultralow-molecular-weight heparin (ULMWH), Arixtra®. (a) The generalized symbolic structure of a typical chain present in porcine intestinal UFH. (b) The chemical structure of Arixtra®, a synthetic ULMWH containing an AT-binding site. Abbreviation: MW, molecular weight.

Figure 2.

Biosynthesis of heparin/heparin sulfate (HS) occurring in the endoplasmic reticulum (ER) and the Golgi.

Figure 3.

Programmable one-pot synthesis of fondaparinux.

Figure 4.

Photochemical depolymerization of heparin. Photochemical reaction with >370 nm light in presence of TiO2 in water produces low-molecular-weight heparin (LMWH) containing a complex mixture of both even and odd numbered chains. This figure contains a few possible example of these chains.

Figure 5.

Mode of action of C5-epimerase.

Figure 6.

Chemoenzymatic synthesis of low-molecular-weight heparins.

Figure 7.

Chemoenzymatic synthesis of the low-molecular-weight heparin (LMWH) containing an internal (¹³C)IdoA2S residue; GlcA-pNP cleavage via alkaline elimination and Smith degradation.