In the past few decades, improved early diagnosis methods, technological developments and an increasing crosstalk between clinicians and researchers has led to the identification of an increasing number of inborn metabolic diseases. In these disorders, missense mutations are the most frequent type of genetic defects, frequently resulting in defective protein folding. A better understanding at the molecular level of protein misfolding and its role in disease has prompted the emergence of therapies based in the use of small molecules that have the ability to correct protein folding defects. Well-known cases are reported for phenylketonuria and Gaucher’s disease. Most of these compounds have a specific mechanism of action interacting directly with a particular protein, the so called pharmacological chaperones. Among such small molecules are protein ligands, either natural substrates or synthetic derivatives, cofactors, competitive inhibitors, and agonist/antagonists. In this review we will start by briefly overviewing the mechanisms through which such ligands exert a stabilizing action, and then move on to an extended discussion on therapeutic approaches and use of vitamins and substrates to correct protein misfolding in metabolic disorders. Examples of vitamins that have been successfully prescribed to rescue some cases of inborn errors of metabolism will be presented. In particular, the role of riboflavin supplementation in the treatment of fatty acid β-oxidation disorders will be thoroughly analyzed, focusing on recent reports that shed light on the molecular basis of vitamin responsiveness. Moreover, we will highlight the latest studies that point to a synergistic effect of cofactors and metabolites in the rescue of defective fatty acid β-oxidation enzymes. The synergism of multiple small molecules may underlie a promising general pharmacological strategy for the treatment of metabolic diseases in general.
|Journal||Current Topics In Medicinal Chemistry|
|Publication status||Published - 1 Jan 2012|