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

Abstract

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.

Clinical and Mutational Characterizations of Ten Indian Patients with Beta-Ketothiolase Deficiency

“…Molecular chaperones, polypeptide unfoldases, can specifically recognize and proofread three-dimensional structures of misfolded/ aggregated proteins and convert them into degradable or rehabilitated, potentially functional, proteins. Stimulation of the latter mechanism using various pharmacological agents may favorably affect functions of misfolded mutant proteins if they have residual enzymatic activities, offering potential hope for a variety of yet untreatable genetic diseases (West et al 2012;Muntau et al 2014;Finka et al 2016). The clinical course of T2-deficient patients whose mutations have some residual enzyme activity, such as GK111 here, does not differ from those whose mutations have no enzymatic activity (Fukao et al 2001).…”

Compromised Catalysis and Potential Folding Defects in in Vitro Studies of Missense Mutants Associated with Hereditary Phosphoglucomutase 1 Deficiency

“…Our data suggest this could be especially pertinent for the four mutants located outside of the active site of PGM1 (N38Y, Q41R, G330R, and L516). Such approaches, including proteasome inhibitors and pharmacological chaperones, are currently being used with success with other metabolic diseases (7,8,19). In contrast, the missense variants associated with severe catalytic defects, as established by these in vitro studies, would likely require additional or alternative approaches, such as enzyme replacement therapy, that could compensate for impaired activity.…”

The molecular basis of galactosemia — Past, present and future

“…Since protein misfolding is likely to be the fundamental cause of most cases of galactosemia, it may be possible to discover molecules which stabilise and promote proper folding of the variant proteins thus increasing enzymatic activity and reducing the tendency to aggregate. Such "pharmacological chaperones" have the potential to restore enzyme activity and alleviate or prevent the bulk of the symptoms (Ringe & Petsko , 2009;Muntau et al , 2014;Brandvold & Morimoto , 2015). This approach has identified compounds which are being used in the successful treatment of cystic fibrosis and transthyretin amyloidoses (Sampson et al , 2011;Bulawa et al , 2012;Hanrahan et al , 2013).…”