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J Med Chem. 2012 Dec 27;55(24):10823-43. doi: 10.1021/jm301182j. Epub 2012 Nov 1.

Small molecules that target protein misfolding.

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BioTherapeutics Chemistry, Pfizer Worldwide Medicinal Chemistry, 200 CambridgePark Drive, Cambridge, Massachusetts 02140, USA.


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.

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