Iminosugars may help advance treatments for Sanfilippo: Cell study
Sugary molecules seen to reduce toxic molecule buildup in cellular disease models
Treatment with sugary molecules called iminosugars can reduce the toxic buildup of heparan sulfate in cellular models of Sanfilippo syndrome, a new study reports.
The study, “N-Substituted l-Iminosugars for the Treatment of Sanfilippo Type B Syndrome,” was published in the Journal of Medicinal Chemistry.
Sanfilippo syndrome is driven by the toxic buildup of the sugar molecule heparan sulfate (HS) inside of cells. Normally, HS is broken down in a cellular compartment called the lysosome, which acts as a cellular “recycling center.” Sanfilippo type B is caused by mutations in a gene called NAGLU which provides instructions for making one of the specialized lysosomal enzymes needed to break down HS.
Iminosugars can interact with enzymes responsible for breaking down sugars
Iminosugars are a group of molecules characterized by a sugar structure with a nitrogen atom replacing an oxygen atom in the ring of the structure. Because their molecular structure resembles a sugar, iminosugars are able to interact with many of the enzymes that are responsible for breaking down sugars like HS.
In some cases, the interaction between iminosugars and enzymes can help to enhance or restore their function. In fact, iminosugars have been developed into therapies for other lysosomal storage disorders, namely Gaucher disease and Niemann-Pick type C disease.
In this study, scientists screened seven iminosugars in cellular models of Sanfilippo syndrome type B.
In cells in which NAGLU gene activity was silenced, the lysosomes become enlarged due to the accumulation of HS, and this abnormal buildup is detectable on the surface of the cells. The researchers found treatment with four of the L-iminosugars — referred to as ent-1, ent-2, ent-6, and ent-7 — led to more normal-appearing lysosomes and reduced the toxic HS buildup.
“These results show, for the first time, that treatment with ent-1, ent-2, ent-6, and ent-7 is able to rescue both lysosomal phenotype and pathological HS accumulation on cell membrane of a cellular model of Sanfilippo B disease,” the researchers wrote.
[The four identified iminosugars] could contribute to the development of an effective treatment of the clinical manifestation of Sanfilippo syndrome.
Iminosugars may be acting as pharmacological chaperones
Similar results were found in other cellular models, including experiments using fibroblasts (cells implicated in the formation of connective tissue) of people with Sanfilippo type B or type A.
In a further series of experiments, the researchers investigated the potential mechanism for these effects. Results suggested that treatment with these iminosugars led to an increase in both levels of the NAGLU protein, as well as the protein’s HS-destroying activity. The iminosugars also appeared to improve transport of the enzyme to the lysosome, where it needs to get to do its job.
The scientists determined that the iminosugars were physically interacting with the enzyme, but were not blocking its active site — the specific spot where the enzyme normally engages with HS to break down the sugar molecule. This suggests that the iminosugars may be acting as pharmacological chaperones, which can bind to the enzyme and help to stabilize it so it can do its job more efficiently.
Overall, the scientists concluded that the four identified iminosugars “could contribute to the development of an effective treatment of the clinical manifestation of Sanfilippo syndrome.”