PHARMACOLOGICAL CHAPERONES AS THERAPEUTIC MODULATORS: A NEW ERA IN PROTEIN MISFOLDING DISEASE MANAGEMENT

Protein misfolding is a central molecular event in many rare genetic and neurodegenerative diseases, leading to the production of unstable, dysfunctional proteins that are often rapidly degraded or form toxic aggregates. Over the past two decades, pharmacological chaperones have emerged as a novel class of small-molecule therapeutics aimed at correcting this defect. These compounds work by selectively binding to misfolded or unstable proteins, stabilizing their structure and assisting in their proper folding, trafficking, and eventual functionality within the cell.Unlike traditional enzyme replacement therapies, pharmacological chaperones act intracellularly and have the potential to cross biological barriers, including the blood-brain barrier, thereby increasing their utility in systemic and neurologic disorders. This review explores the molecular mechanisms by which pharmacological chaperones exert their action and highlights their clinical application across a range of diseases, including Fabry disease, transthyretin amyloid cardiomyopathy and Gaucher disease. In addition to disease-specific benefits, this article discusses broader therapeutic implications and the advantages pharmacological chaperones offer over conventional treatments. Despite their promise, challenges such as mutation specificity, limited organ targeting, potential for enzyme inhibition, and the need for long-term safety data remain areas of active investigation. As our understanding of protein folding disorders expands and technologies for drug discovery improve, pharmacological chaperones are meant to become essential tools in precision medicine especially in many rare conditions.

Keywords: Pharmacological chaperones, Protein misfolding, Lysosomal storage disorders, Mutation-specific therapy, Neurodegenerative diseases, Tafamidis, Migalastat.