The use of pharmacological chaperones in rare diseases caused by reduced protein stability

Abstract

Rare diseases are most often caused by inherited genetic disorders that, after translation, will result in a protein with altered function. Decreased protein stability is the most frequent mechanism associated with a congenital pathogenic missense mutation and it implies the destabilization of the folded conformation in favour of unfolded or misfolded states. In the cellular context and when experimental data is available, a mutant protein with altered thermodynamic stability often also results in impaired homeostasis, with the deleterious accumulation of protein aggregates, metabolites and/or metabolic by‐products. In the last decades, a significant effort has enabled the characterization of rare diseases associated to protein stability defects and triggered the development of innovative therapeutic intervention lines, say, the use of pharmacological chaperones to correct the intracellular impaired homeostasis. Here, we review the current knowledge on rare diseases caused by reduced protein stability, paying special attention to the thermodynamic aspects of the protein destabilization, also focusing on some examples where pharmacological chaperones are being tested.

Amino acid substitutions hydrophilizing the core of titin domains cause dilated cardiomyopathy

“…Specifically, we envision that emerging high-throughput in silico [46][47][48][49] and in vitro 50 methods will be able to capture pathogenicity potential related to domain destabilization of all possible titin missense variants. Identification of these pathogenic variants is a prerequisite for the development of therapies able to counterbalance domain destabilization, including strategies based on exon skipping 51 or pharmacological chaperones 52 . Furthermore, considering the broad functions played by Ig proteins 22 , which indeed are the most common family in the human genome 53 , we propose that searching for hydrophilizing variants as we have done here could benefit management of a wide range of human conditions including other (cardio)myopathies 54,55 , cancer 56 and neurodegeneration 57 .…”

A FRET-Based Assay for the Identification of PCNA Inhibitors

“…A possible therapeutic approach might be the identification of a PCNA stabilizing molecule. Such pharmaceutical chaperones continue gaining importance for the treatment of destabilizing missense mutations [76,77]. Due to the quantities of PCNA interaction partners [8,9], a stabilizer might interfere with the interaction of other binding partners.…”

Review of predicting protein stability changes upon variations

“…This may result in the harmful buildup of protein aggregates, metabolites, or metabolic by‐products, potentially leading to the development of diseases. Research [6] has shown that over 40 different diseases that mainly impact the central nervous system are associated with repeat instability protein mutations, including β‐amyloid protein in Alzheimer's disease [7] and α‐synuclein protein in Parkinson's disease [8]. Therefore, enhancing the thermal stability of proteins is crucial for biomedical and industrial applications.…”