Abstract

Protein folding is an essential biological process that enables proteins to attain their correct three-dimensional structure and perform their physiological functions. Disruptions in protein folding can result in conformational instability, intracellular retention, aggregation, and degradation of proteins, contributing to the development of numerous inherited and acquired diseases. Protein misfolding has been implicated in a wide range of disorders, including lysosomal storage diseases, cystic fibrosis, neurodegenerative disorders such as Alzheimer's and Parkinson's diseases, metabolic disorders, and certain cancers. Conventional therapeutic approaches, including enzyme replacement therapy and symptomatic treatments, often provide limited efficacy because they do not directly address the underlying molecular defects responsible for disease progression. Pharmaceutical chaperones have emerged as a promising therapeutic strategy that targets the root cause of many conformational disorders. These small-molecule compounds selectively bind to unstable or misfolded proteins, stabilize their native conformation, facilitate proper folding, enhance intracellular trafficking, and prevent premature degradation by cellular quality-control mechanisms. Consequently, functional protein levels are restored, leading to improved cellular homeostasis and therapeutic outcomes. The clinical success of migalastat in Fabry disease has validated the potential of pharmaceutical chaperone therapy and stimulated extensive research into its application for other protein misfolding disorders. Recent advances in structural biology, computational drug design, artificial intelligence, and proteostasis research have accelerated the identification and optimization of novel pharmaceutical chaperones with enhanced specificity and efficacy. Additionally, combination approaches involving enzyme replacement therapy, gene therapy, and proteostasis regulators are broadening their therapeutic applications. Despite challenges related to mutation specificity, safety, and target selectivity, pharmaceutical chaperones represent an innovative class of precision therapeutics with significant potential for the treatment of diverse conformational diseases and the advancement of modern drug discovery.