Small Molecules That Target Protein Misfolding

• Published in: Journal of medicinal chemistry 2012-12, Vol.55 (24), p.10823-10843
• Main Authors: Gavrin, Lori Krim, Denny, Rajiah Aldrin, Saiah, Eddine
• Format: Article
• Language: English
• Subjects: alpha 1-Antitrypsin - chemistry; alpha 1-Antitrypsin - physiology; Amyloid - metabolism; Animals; Humans; Models, Molecular; Muramidase - chemistry; Muramidase - physiology; Mutation; Neurodegenerative Diseases - drug therapy; Neurodegenerative Diseases - metabolism; Prealbumin - chemistry; Prealbumin - physiology; Prions - chemistry; Prions - physiology; Protein Binding; Protein Conformation; Protein Folding; Proteins - chemistry; Proteins - physiology; Proteostasis Deficiencies - drug therapy; Proteostasis Deficiencies - metabolism; Receptors, Vasopressin - chemistry; Receptors, Vasopressin - physiology; Serum Amyloid A Protein - chemistry; Serum Amyloid A Protein - physiology; Small Molecule Libraries - chemistry; Small Molecule Libraries - pharmacology; Superoxide Dismutase - chemistry; Superoxide Dismutase - physiology; Superoxide Dismutase-1; Tumor Suppressor Protein p53 - chemistry; Tumor Suppressor Protein p53 - physiology; Unfolded Protein Response
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm301182j

Protein misfolding is a process in which proteins are unable to attain or maintain their biologically active conformation. Factors contributing to protein misfolding include missense mutations and intracellular factors such as pH changes, oxidative stress, or metal ions. Protein misfolding is linked to a large number of diseases such as cystic fibrosis, Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, and less familiar diseases such as Gaucher’s disease, nephrogenic diabetes insipidus, and Creutzfeldt–Jakob disease. In this Perspective, we report on small molecules that bind to and stabilize the aberrant protein, thereby helping it to attain a native or near-native conformation and restoring its function. The following targets will be specifically discussed: transthyretin, p53, superoxide dismutase 1, lysozyme, serum amyloid A, prions, vasopressin receptor 2, and α-1-antitrypsin.