Emerging novel concept of chaperone therapies for protein misfolding diseases

Abstract

Chaperone therapy is a newly developed molecular therapeutic approach to protein misfolding diseases. Among them we found unstable mutant enzyme proteins in a few lysosomal diseases, resulting in rapid intracellular degradation and loss of function. Active-site binding low molecular competitive inhibitors (chemical chaperones) paradoxically stabilized and enhanced the enzyme activity in somatic cells by correction of the misfolding of enzyme protein. They reached the brain through the blood-brain barrier after oral administration, and corrected pathophysiology of the disease. In addition to these inhibitory chaperones, non-competitive chaperones without inhibitory bioactivity are being developed. Furthermore molecular chaperone therapy utilizing the heat shock protein and other chaperone proteins induced by small molecules has been experimentally tried to handle abnormally accumulated proteins as a new approach particularly to neurodegenerative diseases. These three types of chaperones are promising candidates for various types of diseases, genetic or non-genetic, and neurological or non-neurological, in addition to lysosomal diseases.

Lysosomal enzyme replacement therapies: Historical development, clinical outcomes, and future perspectives

“…In those LDs for which the mutations in non-catalytic sites lead to improper folding and triggers their degradation, enzyme enhancement therapy is a valuable approach [101, 102]. This strategy uses pharmacological or molecular chaperones that assist enzymes to fold correctly, thus preventing their degradation, and redirecting them to the lysosome [101, 102]. Examples of pharmacological chaperones include Galafold ™ (Migalastat; 1-deoxygalactonojirimycin) clinically approved for Fabry disease in the E.U.…”

“…Recently, molecules that modulate the function of the molecular chaperone, heat-shock protein 70 (Hsp70), have shown promise for treatment of sphingolipidoses [106, 107]. However, identification of such molecules takes large-scale screening efforts and each molecule is generally specific for just that mutation [102]. Another approach of modulating lysosome trafficking utilizes overexpression of the Rab9 cytosolic molecule, which is linked to endosome maturation and lysosome biogenesis, through gene therapy or protein transduction approaches.…”

Fabry Liga: Klinikinis Atvejis Ir Literatūros Apžvalga

“…Didelės mutacijos lemia visišką baltymo nebuvimą arba defektinis baltymas yra, bet nėra jo katalizinės funkcijos [32]. Farmakologiniai šeperonai, mažos molekulės ligandai, endoplazminiame tinkle gali sujungti ir stabilizuoti mutavusį baltymą.…”

Ambroxol hydrochloride, a chaperone therapy for Paget's disease of bone and other common autophagy-mediated aging diseases?

“…Moreover, it suppresses α-synuclein overexpression neuroblastoma cell lines [2]. Furthermore, it is suggested to be one of chaperone therapies for protein misfolding diseases such as Gaucher disease [4], and for impairment of autophagy-lysosome system occurred in many…”

“…These disorders are known to be related to autophagy machinery impairment [1]. Recent studies have reported roles of Ambroxol hydrochloride in treatment of some oxidative stress induced and autophagy mediated diseases such as Parkinson's disease (PD), related synucleinopathies, Dementia, Alzheimer's, Huntington's, Creutzfeldt-Jakob/prion, and Gaucher (GD) diseases [2][3][4][5][6][7][8].…”