The Non-Drowsy Chaperone

Digging through the recent literature for lysosomal diseases, something caught my attention. I have a bit of an interest in following the progress in finding chaperones for diseases like Sanfilippo syndrome and others. Chaperones are primarily small molecules that may help a protein fold and stabilize it. I first became aware of this when I read the work of the Pshezhetsky lab in Montreal. They showed Glucosamine partially rescued several of the expressed mutants of the lysosomal membrane enzyme, heparan sulfate acetyl-CoA: alpha-glucosaminide N-acetyltransferase responsible for Sanfilippo syndrome MPS IIIC. This meant that they could recover some enzyme activity in these cells.

Chaperones represent a therapeutic approach for many of the rare diseases that are related to the lysosomes. So it was interesting to come across a paper on Ambroxol as a chaperone for mutant glucerebrosidases, which accumulates in lysosomes of patients with Gaucher disease. Ambroxol stimulates synthesis and release of surfactant by type II pneumocytes and is used in cough syrup (hence my rather dry pun title for this post based on a musical). Now there are many chaperones for Gaucher but this one took my interest as its also potent inhibitor of the neuronal Na+ channels and has a very simple structure. This chaperone was first identified in 2009 – (about the same time as glucosamine for MPSIIIC) and being FDA approved has already been the subject of a pilot clinical trial that looked promising as well as studies in the gaucher mouse model. It will be interesting to see how it progresses.

So of course this make me wonder. Why not pursue glycosamine in pilot clinical studies for MPSIIIC?

During my search I also dug out a paper on oxysterol derived chaperones of Niemann-Pick type C1. Again the substituents appended to the core sterol structure are pretty simple.

This may suggest that looking at FDA approved drugs that are similar to these analogs (namely steroidal compounds) may be worthwhile, e.g. an exhaustive search, in order to find compounds that can be repurposed and progressed quickly in clinical studies. I am not aware from my searches that such a screen of steroids has been performed.

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