Carbohydrate drugs (Part 6) (Polysaccharides)

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Polysaccharides are polymeric carbohydrate structures. The monomers are linked via glycosidic bonds. Some common examples are starch, glycogen or cellulose.

In this topic we will mainly talk about glycosaminoglycans (GAGs), highly sulfated, long unbranched polysaccharides composed of repeating disaccharide units with important biological roles. Based on the difference of repeating disaccharide units, they can be classified into four main groups: heparin/heparan sulfate, chondroitin sulfate/dermatan sulfate, hyaluronan and keratan sulfate1.

We will talk about the first three categories.

Heparin/heparan sulfate

Native heparin is a polysaccharide with an average molecular weight of 12-15 kDa. It is composed of repeating disaccharide units. The most common building block is composed of a 2-O-sulfated iduronic acid and 6-O-sulfated, N-sulfated glucosamine (Fig. 1). Because of the many sulfate groups – that are in anionic form at physiological pH levels -heparin is the most negatively charged macromolecule in the body. The difference between heparin and heparan sulfate is summarized in the table below2:

hepvshs

hep

Fig.1: 2-O-sulfated iduronic acid and 6-O-sulfated, N-sulfated glucosamine, the most common disaccharide unit of heparin

Heparin acts as an anticoagulant, and it is used in several diseases, like acute coronary syndrome or deep-vein thrombosis, however its physiological role is yet unknown, since blood anticoagulation is achieved mostly by heparan sulfate proteoglycans derived from endothelial cells.

Native (unfractioned) heparin (UFH) has several adverse effects, bleeding (nose and gums), heparin induced thrombocytopenia (HIT) that can be a common immune complication. That is why other heparin analogues have been developed. Low-molecular-weight heparins (LMWH, e.g. enoxaparin, fondaparinux, dalteparin) have undergone fractionation (depolymerization) for the purpose of making their pharmacodynamics more predictable. LMWHs are still polysaccharides, but with less molecular weight (average is 4.5 kDa). All heparins are administered as subcutaneous injections.

The sole antidote of heparins is protamine, an arginine-rich oligopeptide, however its administration should be monitored and also it is most effective against natural heparin. Because of these reasons there is a need for new type of heparin antidotes. Cationic cyclodextrin derivatives could be promising as potential heparin antidotes3.

Chondroitin sulfate

It is composed of alternating N-acetylgalactosamine and glucuronic acid which bear 4-O- and/or 6-O-sulfations at the N-acetylgalactosamine units disposed of in specific patterns (2). (Some glucuronic acid residues are epimerized into L-iduronic acid and the resulting disaccharide is then referred to as dermatan sulfate).  Because of its structure it retains water. Chondroitin sulfate can be found in the body as important structural component of cartilage. Chondroitin sulfate and dermatan sulfate are synthesized as galactosaminoglycan polymers and are covalently attached (by a common tetrasaccharide sequence) to the serine residues of core proteins. Sulfation of the chondroitin polymer by specific sulfotransferases occurs as the polymer is being formed4.

chondr

Fig. 2: A disaccharide unit of chondroitin sulfate

Along with glucosamine or methylsulfonylmethane (MSM) it is widely used in OTC drugs and dietary supplements for the treatment of osteoarthritis. Several clinical studies have been performed (e.g. the LEGS study5) to get more knowledge about its role in osteoarthritis and whether it is effective taken orally (or not). Most of the studies showed that chondroitin sulfate is not more effective than placebo, however more research is needed (especially because of the small number of people involved)6.

Hyaluronic acid

It is a polysaccharide composed of D-glucuronic acid and N-acetyl-D-glucosamine (3), linked via alternating β-(1→4) and β-(1→3) glycosidic bonds. Like chondroitin sulfate, hyaluronic acid also retains water. It is synthetized by hyaluronan synthases. Its structure differs from the other GAGs by the lack of sulfated groups and also hyaluronic acid has the highest molecular weight among GAGs (up to 700 kDa)7.

HA

Fig. 3: A building block of hyaluronic acid: D-glucuronic acid and N-acetyl-D-glucosamine linked with β-(1→3) glycosidic bond

Hyaluronic acid has several physiological functions. It is a component of articular cartilage and skin, it is abundant in wounded tissue, it has a key role in inflammation response and angiogenesis, its level can be a marker in a few types of cancer (e.g. breast or prostate).

As for pharmaceutical usages of hyaluronic acid:

  • It can be used for the treatment of osteoarthritis of the knee by direct injection into the joint (FDA approved) also in veterinary (e.g. for horses).
  • It is a component of artificial tears.
  • Hyaluronic acid is a component of creams and ointments for atopic skin.

Cosmetic industry also uses a lot of hyaluronic acid.

This was the last part of the carbohydrate drugs and we could see a bit of insight how diverse carbohydrates can be as active pharmaceutical ingredients.

 

 

1 Zhang, F. et al. Glycosaminoglycans, Handbook of Glycomics, Chapeter Three, 2009, Academic Press

2 https://www.sigmaaldrich.com/technical-documents/articles/biology/what-is-heparin.html

3 https://cyclolab.hu/userfiles/LMWH%20antidote.pdf

4 Silbert, J.E.; Sugumaran, G. Biosynthesis of chondroitin/dermatan sulfate, IUBMB Life, 2002, 54(4):177-186

5 https://clinicaltrials.gov/ct2/show/NCT00513422

https://www.arthritis.org/living-with-arthritis/treatments/natural/supplements-herbs/glucosamine-chondroitin-osteoarthritis.php

7 Cyphert, J.M. et al. Size Matters: Molecular Weight Specificity of Hyaluronan Effects in Cell Biology, Int J Cell Biol, 2015, ID 563818

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