Chaperone therapy was proposed as a new molecular therapeutic
approach almost simultaneously to lysosomal diseases and cystic fibrosis, caused by
gene mutations resulting in misfolding of expressed proteins. In our original papers,
we reported that unstable mutant lysosomal enzymes causing lysosomal diseases
resulted in rapid intracellular degradation and loss of catalytic function. However, in
the presence of some low molecular competitive inhibitors (chemical chaperones),
after binding to enzyme active sites, paradoxically stabilized and enhanced catalytic
activities in somatic cells (proteostasis) by correcting the enzyme protein folding.
After oral administration, they were transferred to the bloodstream, reached the
brain tissue through the blood-brain barrier, and normalized pathophysiology of the
disease. Our reports of these inhibitory chaperones were followed by reports of non-competitive (or
allosteric) chaperones without inhibitory bioactivity. Furthermore heat shock proteins and other
endogenous proteins were recognized as candidates for the third-type chaperone therapy. Theoretically
they could be utilized for handling abnormally accumulated intracellular mutant proteins, if they are
overexpressed by small molecules particularly in neurodegenerative diseases. These three types of
chaperone therapies are expected as promising approaches to a variety of diseases, genetic or nongenetic,
and neurological or non-neurological, in addition to lysosomal diseases. Finally, in this article,
possible chaperones for Gaucher disease are discussed, and preliminary clinical results of ambroxol
therapy are summarized.
Keywords: Chaperone therapy, inhibitory chaperone, allosteric chaperone, molecular chaperone, protein misfolding, lysosomal
disease, Gaucher disease.
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