Structure-guided discovery of pharmacological chaperones targeting protein conformational and misfolding diseases

Protein structure information at the atomic level has provided enabling starting points for the rational design of small-molecule drugs. Structural biology is also applied to the emerging field of pharmacological chaperone (PC) therapy, a paradigm approach using target-specific small molecules for the treatment of diverse protein conformational and misfolding diseases. PCs play the role of a corrector to stabilize folding conformations of the defective protein and an escort for its trafficking and delivery to the destination. This chapter illustrates how the PC field has exploited experimental structures of disease-associated variant proteins to elucidate molecular principles underlying the protein stabilization and folding defects and of protein-ligand complexes to understand the chaperoning effects of PC molecules in development. The fast-paced technological advances and evolution of the PC concept paves the way for using structure determination methods as a primary assay to screen compound libraries and identify the next generation of PCs.