Innovative strategies to treat protein misfolding in inborn errors of metabolism: pharmacological chaperones and proteostasis regulators

• Published in: Journal of inherited metabolic disease Vol. 37; no. 4; pp. 505 - 523
• Main Authors: Muntau, Ania C., Leandro, João, Staudigl, Michael, Mayer, Felix, Gersting, Søren W.
• Format: Journal Article Conference Proceeding
• Language: English
• Published: Dordrecht Springer Netherlands 01.07.2014; Springer; Blackwell Publishing Ltd
• Subjects: Animals; Biochemistry; Biological and medical sciences; Drug Delivery Systems; Endoplasmic Reticulum-Associated Degradation - physiology; Human Genetics; Humans; ICIEM Symposium 2013; Internal Medicine; Kinetics; Medical genetics; Medical sciences; Medicine; Medicine & Public Health; Metabolic Diseases; Metabolism, Inborn Errors - complications; Metabolism, Inborn Errors - metabolism; Metabolism, Inborn Errors - therapy; Molecular Chaperones - pharmacology; Molecular Chaperones - therapeutic use; Pediatrics; Protein Folding - drug effects; Proteins - chemistry; Proteins - metabolism; Proteostasis Deficiencies - complications; Proteostasis Deficiencies - metabolism; Proteostasis Deficiencies - therapy; Fabry Disease; Enzyme Replacement Therapy; Protein Misfolding; Gauche Disease; Cystic Fibrosis Transmembrane Conductance Regulator; Nutrition; Chaperone; Metabolic diseases; Regulator; Enzymopathy; Congenital disease; Protein; Genetic disease; Innovation; Regulation(control); Treatment; Genetics; Strategy
• ISSN: 0141-8955; 1573-2665
• DOI: 10.1007/s10545-014-9701-z

To attain functionality, proteins must fold into their three-dimensional native state. The intracellular balance between protein synthesis, folding, and degradation is constantly challenged by genetic or environmental stress factors. In the last ten years, protein misfolding induced by missense mutations was demonstrated to be the seminal molecular mechanism in a constantly growing number of inborn errors of metabolism. In these cases, loss of protein function results from early degradation of missense-induced misfolded proteins. Increasing knowledge on the proteostasis network and the protein quality control system with distinct mechanisms in different compartments of the cell paved the way for the development of new treatment strategies for conformational diseases using small molecules. These comprise proteostasis regulators that enhance the capacity of the proteostasis network and pharmacological chaperones that specifically bind and rescue misfolded proteins by conformational stabilization. They can be used either alone or in combination, the latter to exploit synergistic effects. Many of these small molecule compounds currently undergo preclinical and clinical pharmaceutical development and two have been approved: saproterin dihydrochloride for the treatment of phenylketonuria and tafamidis for the treatment of transthyretin-related hereditary amyloidosis. Different technologies are exploited for the discovery of new small molecule compounds that belong to the still young class of pharmaceutical products discussed here. These compounds may in the near future improve existing treatment strategies or even offer a first-time treatment to patients suffering from nowadays-untreatable inborn errors of metabolism.