Small molecules that target protein misfolding.
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.
BioTherapeutics Chemistry, Pfizer Worldwide Medicinal Chemistry, 200 CambridgePark Drive, Cambridge, Massachusetts 02140, USA.
Lori Krim
LK
Gavrin
Rajiah Aldrin
RA
Denny
Eddine
E
Saiah
D000682:Amyloid / Q000378:metabolism; D000818:Animals; D006801:Humans; D008958:Models, Molecular; D009113:Muramidase / Q000737:chemistry / Q000502:physiology; D009154:Mutation; D019636:Neurodegenerative Diseases / Q000188:drug therapy* / Q000378:metabolism; D011228:Prealbumin / Q000737:chemistry / Q000502:physiology; D011328:Prions / Q000737:chemistry / Q000502:physiology; D011485:Protein Binding; D011487:Protein Conformation; D017510:Protein Folding; D011506:Proteins / Q000737:chemistry* / Q000502:physiology*; D057165:Proteostasis Deficiencies / Q000188:drug therapy* / Q000378:metabolism; D017483:Receptors, Vasopressin / Q000737:chemistry / Q000502:physiology; D000685:Serum Amyloid A Protein / Q000737:chemistry / Q000502:physiology; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000494:pharmacology; D013482:Superoxide Dismutase / Q000737:chemistry / Q000502:physiology; D000072105:Superoxide Dismutase-1; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000502:physiology; D056811:Unfolded Protein Response; D000515:alpha 1-Antitrypsin / Q000737:chemistry / Q000502:physiology
D000682:Amyloid; D011228:Prealbumin; D011328:Prions; D011506:Proteins; D017483:Receptors, Vasopressin; C000606290:SOD1 protein, human; D000685:Serum Amyloid A Protein; D054852:Small Molecule Libraries; D016159:Tumor Suppressor Protein p53; D000515:alpha 1-Antitrypsin; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D009113:Muramidase