Pharmacologic Chaperone Therapy Targets Gaucher Disease

A recent publication described finding three inhibitors of the enzyme glucocerebrosidase (GC) that were able to function as pharmacological chaperones to reactivate mutant forms of the enzyme that are found in Gaucher disease, a rare autosomal recessive lysosomal storage disorder.

Gaucher disease is caused by the absence, or near absence, of GC activity. The normal action of the 55.6 kD, 497 amino acids long GC is to break down glucocerebroside, a cell membrane lipid constituent. If not broken down, glucocerebroside accumulates in certain cells to levels that can cause damage, especially in the spleen, liver, and bone. The macrophages that clear these cells are unable to eliminate the waste product, which builds up in fibrils, and turn into Gaucher cells, which appear on light microscopy as appearing to contain crumpled-up paper.

A pharmacologic chaperone is a relatively new concept in the treatment of certain genetic diseases. Small molecules that stabilize correct protein folding are administered to the patient, which results in a recovery of enzyme function lost due to mutation.

Pharmacologic chaperone therapy presents an attractive alternative to--due its low risk--and to enzyme replacement therapy--due to lowered expense and oral availability. Most pharmacologic chaperones are inhibitors of the enzyme targeted, but because of differing conditions in the target's destination (pH, metal ions, etc.) the inhibitor is ejected, and the enzyme functions. Alternatively, the relatively high concentration of substrate out-competes the inhibitor; or a combination of both effects enables the enzyme to function. Even if the chaperone continued to inhibit the enzyme, for most of these diseases an inhibited amount of enzyme would be much better than none at all.

Investigators at the [U.S.] National Institutes of Health (Bethesda, MD, USA) used quantitative high-throughput technology to screen more than 60,000 individual compounds at numerous concentrations to determine each molecule's effect on the ability of QC to break down a fluorescent version of its lipid target. They reported in the August 1, 2007, online edition of the Proceedings of the [U.S.] National Academy of Sciences that they had found three classes of compounds that previously had not been considered as therapeutics for Gaucher disease, including sulfonamides, which have been used as antibiotics, aminoquinolines, and triazines.

"These classes of molecules may actually salvage the patients' own defective enzyme,” said senior author Dr. Ellen Sidransky, a senior investigator at NIH. "In Gaucher disease, most of the mutations that cause the disease change a single amino acid in the enzyme. This results in a misfolded protein, which either does not work right or is discarded before it reaches the lysosome. The newly identified molecules, called chemical chaperones, bind to the enzyme and stabilize its shape, enabling it to get to the lysosome where it can then act to break down the storage products. The screening process showed which shape-changing molecules best restored the enzyme's normal function.”


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National Institutes of Health