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Fabry disease
Published in William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop, Atlas of Inherited Metabolic Diseases, 2020
Activation of mutant enzymes by compounds such as 1-deoxygalactonojirimycin are being explored in novel approaches to the treatment of glycosphingolipidoses [76, 77]. This compound is an inhibitor of lysosomal α-galactosidase but, in low doses, it serves as an activator increasing activity in mutant enzymes up to 14 times. These compounds have been referred to as chemical chaperones, because they accelerate transport and maturation of the enzyme molecule. Chaperone therapy with migalastat was found to confer results equal to enzyme replacement therapy [78, 79]. Renal, cardiac, or cerebrovascular events continued to occur in both groups but results were encouraging for mono therapy. A pharmacogenetic test in which mutations were expressed in HEK cells identified mutations amenable to treatment with migalastat [80].
Current and future CFTR therapeutics
Published in Anthony J. Hickey, Heidi M. Mansour, Inhalation Aerosols, 2019
Marne C. Hagemeijer, Gimano D. Amatngalim, Jeffrey M. Beekman
It remains uncertain whether correction of F508del-CFTR by chemical chaperones alone may eventually reach sufficient CFTR function to prevent further progression of CF. Combinations of chemical chaperones with small molecules that target F508del using distinct modes of action such as amplifiers or RNA-targeting approaches may turn out to be essential. For now, the encouraging phase II data of triple combination therapy support the hope that efficacious F508del modulator therapies will become available in the coming decade for the approximately 85% of individuals with CF that have a single F508del allele.
Experimental and investigational drugs for the treatment of alpha-1 antitrypsin deficiency
Published in Expert Opinion on Investigational Drugs, 2019
Chemical chaperones are a group of molecules that guide folding and may reverse cellular mislocalization of proteins. Several generic chaperones have had an effect in pre-clinical studies relevant to AATD; 4-phenylbutyric acid (PBA) mediated an increase in secretion of functionally active Z-AAT in cell culture and murine models [108] and trimethylamine N-oxide (TMAO) stabilized both native M-AAT and Z-AAT against heat-induced polymerization, but did not aid refolding of denatured AAT [109], nor did they augment secretion [108]. PBA went on to be used in two small human studies in AATD patients. An open-label study in 10 patients over 2 weeks resulted in no change in AAT level and was poorly tolerated, with multiple side effects being seen [110]. Another Phase I study in PiZZ AATD enrolled a total of 11 patients and mean serum AAT levels increased from baseline in the first five subjects after receiving 5, 10, and 20 g/day of 4-PBA, suggesting a biological effect. However, short-term use of up to 40 g/day did not result in a meaningful increase in AAT levels and again significant adverse events were reported [111].
Pharmacoperone drugs: targeting misfolded proteins causing lysosomal storage-, ion channels-, and G protein-coupled receptors-associated conformational disorders
Published in Expert Review of Clinical Pharmacology, 2018
Zhi-Shuai Hou, Alfredo Ulloa-Aguirre, Ya-Xiong Tao
A chaperone means ‘one who goes along with another in order to assure proper behavior.’ The term pharmacoperone (pharmacological chaperone or pharmacochaperone) is proposed to define a small molecule that is able to cross the cell surface PM and reach its target protein (either a misfolded or a destabilized, aggregation-prone protein) within the cell, serving as a molecular scaffold for aiding the protein to stabilize its native fold and prevent its aggregation and degradation via the polyubiquitination-proteasome pathway [4–6,60,61]. Since protein misfolding accounts for a large variety of protein conformational diseases, PCs represent a unique therapeutic opportunity to directly correct routing and rescue function of the mutant proteins, potentially curing disease [6]. In contrast with chemical chaperones, which are non- or poorly specific [61,62], PCs have the advantage of selective binding to the conformationally abnormal protein, which allows degradation of other misfolded proteins that should be eliminated by the cell as part of the normal process of biosynthesis and QCS [2,61,63,64] . Chemical chaperones, which also are small-molecular weight compounds, promote folding by stabilizing the molecular conformation of the misfolded protein without interacting with it or interfering with its function [61,65]. Chemical chaperones usually require high concentrations for promoting effective folding of mutant proteins, which makes them too toxic for in vivo applications for therapeutic purposes, albeit with some exceptions.
Protein misfolding, ER stress and chaperones: an approach to develop chaperone-based therapeutics for Alzheimer’s disease
Published in International Journal of Neuroscience, 2023
Rimaljot Singh, Navpreet Kaur, Neelima Dhingra, Tanzeer Kaur
Chaperones oversee the error-free folding of the proteins and thus help in preventing their misfolding and aggregation, and finally assuring their trafficking and function. Broadly, chaperones can be classified into three categories i.e. molecular, chemical, and pharmacological chaperones. Molecular chaperones are mainly ER-resident proteins, which assist in the proper folding of proteins in the cell. In recent years small molecules known as chemical chaperones have been shown to effectively reduce the number of misfolded proteins. These chemical chaperones mimic the functions of intracellular molecular chaperones. The chemical chaperones specifically hydrophobic chaperones, interact with the hydrophobic region of the unfolded or misfolded proteins and prevent their aggregations.