Carbohydrate drugs (Part 5) (Oligosaccharides, cyclodextrins)

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First let’s talk about one of the biggest achievements in the history of cyclodextrin research: Sugammadex.

Sugammadex (SGM) (BridionTM) (1a) is a cyclic oligosaccharide, composed of eight α-D-glucose units (a modified γ-cyclodextrin). All the primary hydroxyl groups are substituted with 3-mercaptopropionic acid, the secondary ones are unsubstituted. It is a single isomer.

Ok, but why is such a big deal?

This is the first molecule that is the specific antidote of rocuronium, an aminosteroid non-depolarizing neuromuscular-blocking agent, used in anesthesia1. It is also effective against vecuronium and pancuronium, but with less affinity towards them (we should mention that neostigmine also suspends the effect of these aminosteroids, but it is not as effective as sugammadex).

Another advantage over neostigmine is, that SGM doesn’t inhibit the acetylcholinesterase enzyme, thus there is no need to deal with the cholinergic effects.

Its mechanism of action is encapsulation, and the formed complex (1:1) is one of the strongest that can occur between a cyclodextrin and a guest molecule. The carboxyl groups are deprotonated at physiological pH levels and form electrostatic bonds with the quaternary N of the aminosteroid (1b)1.

sgm

Structure of sugammadex (1a) and its mechanism of action (1b)2

Its synthesis is really difficult and SGM has to be purified from several process-related intermediates/impurities. Today several high purity, process related starting materials, standards and impurities are available3.

2-Hydroxypropyl-beta-cyclodextrin (HPBCD) (2) is a randomly substituted beta-cyclodextrin derivative. Its degree of substitution (the hydroxypropyl units per molecule) can vary between a wide range, according to the USP (2.8-10.5).

hpbcd

HPBCD (2)

HPBCD is an orphan drug approved by both FDA (2010) and EMA (2011) for the treatment of NPC disease, a lysosomal storage disease with wide clinical spectrum4. Mutation of NPC1 and NPC2 genes are associated with NPC. The NPC1 gene encodes a protein that is located in membranes inside the cell and is involved in the movement of cholesterol and lipids within cells, while NPC2 encodes a protein that binds and transports cholesterol. As a result of these mutations abnormal buildup of lipids and cholesterol accumulate within cell membranes. Currently this disease is incurable, but there are a few molecules that can help improve the quality of life of people who have NPC.

Although the exact mechanism is not known, the reduced level of cholesterol in the brain of the children suffering in this rear disease shows that HPBCD has an influence on the cholesterol accumulation and metabolism5. Treatment involves a combination of intravenous therapy (IV), intrathecal therapy (IT) and intracerebroventricular (ICV) HPBCD therapy.

On this blog you can read several other articles about cyclodextrins and NPC, including the latest researches.

Another important, non-cyclodextrin oligosaccharide is Acarbose (3), an alpha-glucosidase inhibitor. (In the second part, we also mentioned a few monosaccharide-type alpha-glucosidase inhibitors used to treat type 2 diabetes6). The molecule reversibly binds to pancreatic alpha-amylase and membrane-bound intestinal alpha-glucoside hydrolases. Thus, inhibiting the enzyme complex, the hydrolysis of di-, tri- and oligosaccharides are blocked. It is composed of a specific disaccharide acarviosin and a maltose at the reducing end.

acarbose

Acarbose (3)

We can find other oligosaccharides with active pharmacological effects, e.g, among the low-molecular-weight heparins (LMWH), however, most of them are rather polysaccharides, so we will discuss them later.

References

1 Bom, A. et al. A novel concept of reversing neuromuscular block: chemical encapsulation of rocuronium bromide by a cyclodextrin-based synthetic host. Angew Chem, Intern Ed, 2002, 41(2), 265-270

2 Srivastava, A and Hunter, J.M: Reversal of neuromuscular block, Br J Anaesth, 2009, 103(1):115-129

3 https://cyclolab.hu/products/analytical_standards-c20

4 Walkley, S.U., Davidson, C.D., Jacoby, J., (…), Vite, C.H., Ory, D.S. Fostering collaborative research for rare genetic disease: The example of niemann-pick type C disease. Orphanet J. Rare Dis. 2016, 11(1), 161

5 Tanaka, Y. et al. Efficacy of 2-Hydroxypropyl-β-cyclodextrin in Niemann–Pick Disease Type C model mice and its pharmacokinetic analysis in a patient with the disease, Biol Pharm Bull, 2015, 38:844–851

6 https://cyclodextrinnews.com/2019/05/15/carbohydrate-drugs-part-2-iminosugars-and-rare-diseases/

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