Title:Protein Misfolding in Disease and Small Molecule Therapies
VOLUME: 12 ISSUE: 22
Author(s):Claudio M. Gomes
Affiliation:ITQB/UNL, Av. Republica 127, 2780-756 Oeiras, Portugal.
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
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.
