Protein Misfolding in Disease and Small Molecule Therapies

Claudio      M. Gomes

Abstract

A large number of human disorders are caused by defects in protein folding resulting from genetic mutations or adverse physiological conditions, and these are collectively referred to protein misfolding diseases. Such disorders imply dysfunction of a cellular process either as a result of a toxic gain of function due to protein aggregation, or loss of function due to protein instability, inefficient folding or defective trafficking. For a number of cases, drugs acting directly on the affected protein have been found to prevent misfolding and rescue function. This brief review will illustrate molecular mechanisms through which small molecules acting as folding correctors can prevent excessive protein buildup or recover faulty protein conformers, thus acting as effective therapeutic pharmacological chaperones. As background, the principles underlying the thermodynamics and kinetics of the protein folding reaction will be overviewed, as well as pathways leading to the formation of misfolding. The mechanism of action of small molecule correctors will then be discussed in light of these basic principles using illustrative examples referring to drugs that are effective over proteins involved in trafficking and folding diseases, amyloid aggregation disorders and metabolic deficiencies. An outlook on synergistic effects between different folding correctors and their combination with proteostasis regulators will also be addressed, as a relevant strategy towards the design of more effective therapies against protein folding diseases.

Keywords: Protein folding, protein aggregation, protein stability, amyloid, pharmacological chaperone, folding correctors, proteostasis, neurodegenerative diseases, metabolic diseases, lysosomal diseases, alzheimer’s disease, amyotrophic lateral sclerosis, familial amyotrophic polyneuropathy, loss of function, toxic gain of function, tafamidis, VX-809, isofagomine, migalastat, duvoglustat, tetrahydrobiopterin, riboflavin