Small molecules as therapeutic agents for inborn errors of metabolism

Abstract

Most inborn errors of metabolism (IEM) remain without effective treatment mainly due to the incapacity of conventional therapeutic approaches to target the neurological symptomatology and to ameliorate the multisystemic involvement frequently observed in these patients. However, in recent years, the therapeutic use of small molecules has emerged as a promising approach for treating this heterogeneous group of disorders. In this review, we focus on the use of therapeutically active small molecules to treat IEM, including readthrough agents, pharmacological chaperones, proteostasis regulators, substrate inhibitors, and autophagy inducers. The small molecules reviewed herein act at different cellular levels, and this knowledge provides new tools to set up innovative treatment approaches for particular IEM. We review the molecular mechanism underlying therapeutic properties of small molecules, methodologies used to screen for these compounds, and their applicability in preclinical and clinical practice.

Protein misfolding diseases: Prospects of pharmacological treatment

“…Enzyme cofactors provide another type of PC. An increase in the amount of the natural cofactor of an enzyme might help stabilize it . Such is the case of (6R)‐ l ‐erythro‐5,6,7,8‐tetrahydrobiopterin (BH 4 ), the natural cofactor of phenylalanine hydroxylase (PAH), the defective enzyme in phenylketonuria (PKU) .…”

“…The gathering of computational evidence, such as that afforded by FoldX or residue location analysis, together with experimental evidence regarding the oligomeric state of the mutant protein and its stability, are necessary steps in determining whether a missense variation alters a protein's folding. The fact that PRs act within the protein homeostasis network rather than directly on any specific protein may render them valuable against a whole group of diseases that alter a particular process in a similar fashion …”

“…In total, around 40 PCs have been described as effective in the treatment of different IEMs, most of them for LSDs, but of these only few are used clinically or are under pharmaceutical development (Table ).…”

“…An increase in the amount of the natural cofactor of an enzyme might help stabilize it. 45 Such is the case of (6R)-L-erythro-5,6,7,8-tetrahydrobiopterin (BH 4 ), the natural cofactor of phenylalanine hydroxylase (PAH), the defective enzyme in phenylketonuria (PKU). 46,47 Additionally, endogenous Hsp can be used for the stabilization of mutant proteins in some diseases by using molecular chaperone inducers.…”

“…The fact that PRs act within the protein homeostasis network rather than directly on any specific protein may render them valuable against a whole group of diseases that alter a particular process in a similar fashion. 45 3.1 | Neurodegenerative diseases caused by misfolded functional proteins…”