Small-molecule modulation of cellular chaperones to treat protein misfolding disorders.
The correct folding of proteins is a fundamental process in the normal physiological functioning of cells, and is mediated by cellular chaperones including members of the Hsp70 family. Many diseases are caused by a failure of cellular chaperones to adequately maintain correct protein folding, and has led to the development of a therapeutic strategy to upregulate the activity of cellular chaperones in order to ameliorate intrinsic folding deficits. A large range of pharmacological agents that can induce cellular chaperones and correct deficits associated with misfolded proteins are known. This review surveys the mechanisms and compounds that have been used to modulate cellular chaperones, and discusses the continuing challenges in translating this approach into clinical improvements in the treatment of protein misfolding disorders.
Sloan
Lisa A
LA
Department of Discovery Medicinal Chemistry, GlaxoSmithKline Medicines Research Centre, Stevenage, UK. Lisa.A.Sloan@gsk.com
Fillmore
Martin C
MC
Churcher
Ian
I
D000818:Animals; D015195:Drug Design; D015316:Genetic Therapy; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D006898:Hydroxylamines / Q000494:pharmacology; D018832:Molecular Chaperones / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015394:Molecular Structure; D011487:Protein Conformation; D017510:Protein Folding / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D057165:Proteostasis Deficiencies / Q000235:genetics / Q000378:metabolism* / Q000628:therapy; D013329:Structure-Activity Relationship; D015854:Up-Regulation
D018840:HSP70 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins; D006898:Hydroxylamines; D018832:Molecular Chaperones