Small Molecules: Substrate Inhibitors, Chaperones, Stop-Codon Read Through, and Beyond

ABSTRACT

Abstract Lysosomal storage disorders are rare genetic disorders due to deficient lysosomal activity, which leads to progressive accumulation of nonmetabolized substrates. Patient's clinical outcomes have significantly improved since the advent of enzyme replacement therapy, even though this therapeutic approach presents important limitations, such as immune reactions, low bioavailability of recombinant enzymes, and incapability to reach the central nervous system. New strategies based on gene therapy or small molecules have been proposed and tested as an alternative to enzyme replacement therapy or to complement it. Small molecules are orally administrated, no antigenic compound that can diffuse across cell membranes and distribute in steady-state concentrations, also reaching the central nervous system. Substrate reduction therapy, pharmacological chaperones, and stop-codon read-through enhancers are small molecules currently available for the treatment of lysosomal storage disorders. This article describes the characteristics of this class of compounds and the possible strategies to improve their efficiency in future development.