In the part 1 we talked about monosaccharides used for the treatment of common diseases, like influenza or angina pectoris. Now let’s take a look at a few rare diseases.
What is a rare disease? Any disease that affects a small percentage of the population, most of them are genetic.
The Fabry-disease (Anderson–Fabry disease) is an X-chromosome linked, lysosomal storage disease, characterized by the deficiency of the enzyme alpha-galactosidase A (α-GAL A). As a result, globotriaosylceramide accumulates in several part of the body: skin, heart, kidney. Among the symptoms the most serious are pain, fatigue, neuropathy and angiokeratomas (small, painless papules). Fabry disease affects an estimated 1 in 40.000 to 60.000 males1.
The Gaucher disease is also a lysosomal storage disease, involving the glucocerebrosidase enzyme, that hydrolyzes glucocerebroside. This disorder can be characterized by anemia, fatigue, spleen and liver enlargement. The prevalence is approximately 1/100.000. The annual incidence of Gaucher disease in the general population is about 1/60.000, but it can reach up to 1/1.000 in Ashkenazi Jewish populations2.
Ok, but how do monosaccharides come to these rare diseases?
Iminosugars are sugar analogues, where a nitrogen atom replaces the ring oxygen. 1-deoxynojirimycin (1) is a natural compound, found in mulberry leaves (Morus spp). The compound itself has pharmacological activity; it is an inhibitor of the alpha-glucosidase enzyme.
Migalastat (Galafold®) (2) is a derivative of 1, used for the long-term treatment of Fabry disease. It is a pharmacological chaperon, works only in the amenable mutation of the enzyme (when the protein is misfolded, but the function can be restored).
Miglustat (3) (Zavesca®) is also a derivative of 1-deoxynojirimycin, it can be used in Gaucher disease type 1, as substrate replacement therapy; the molecule prevents the formation of glucocerebroside. We should mention, that miglustat is the first treatment to be approved for treating progressive neurological complications in people with Niemann–Pick disease, type C4.
There is another 1-deoxynojirimycin derivative, miglitol (4) (Glyset®) used in the treatment of type II diabetes. It is an alpha-glucosidase inhibitor too, reducing the rate of digestion of complex carbohydrates; thus, less glucose is absorbed.
1-deoxynojirimycin is in the focus of interest, several derivatives are under development, e.g. for the treatment of viral infections5.
For the sake of completeness, we should mention two more alpha-glucosidase inhibitors: voglibose (Voglib®) and acarbose (Glucobay®). The former one is a cyclic sugar alcohol with a hydroxyl group replaced by an amino group (aminocyclitol). Acarbose is an oligosaccharide, composed from acarviosin and two maltose units (to be shown in a later post). Voglibose is the newest molecule from the above mentioned two compounds.
All these drugs are taken orally.
In part 3 we go further into the carbohydrates and talk a little bit about disaccharide type drugs.
3 Inouye, S.; Tsuruoka, T.; Ito, T. and Niida, T. Structure and synthesis of nojirimycin. Tetrahedron. 1968, 24 (5): 2125
4 Pineda, M; Walterfang, M and Patterson, M. Miglustat in Niemann-Pick disease type C patients: a review, Orphanet J Rare Dis 2018, 13:140
5 Iminosugars and methods of treating viral diseases US9943532B2