title: Selective inhibition of extracellular thioredoxin by asymmetric disulfides.
abstract: Whereas the role of mammalian thioredoxin (Trx) as an intracellular protein cofactor is widely appreciated, its function in the extracellular environment is not well-understood. Only few extracellular targets of Trx-mediated thiol-disulfide exchange are known. For example, Trx activates extracellular transglutaminase 2 (TG2) via reduction of an intramolecular disulfide bond. Because hyperactive TG2 is thought to play a role in various diseases, understanding the biological role of extracellular Trx may provide critical insight into the pathogenesis of these disorders. Starting from a clinical-stage asymmetric disulfide lead, we have identified analogs with >100-fold specificity for Trx. Structure-activity relationship and computational docking model analyses have provided insights into the features important for enhancing potency and specificity. The most active compound identified had an IC(50) below 0.1 μM in cell culture and may be appropriate for in vivo use to interrogate the role of extracellular Trx in health and disease.
authors: Department of Chemical Engineering, Stanford University , Stanford, California 94305, USA.
authors: Thomas R
authors: TR
authors: DiRaimondo
authors: Nicholas M
authors: NM
authors: Plugis
authors: Xi
authors: X
authors: Jin
authors: Chaitan
authors: C
authors: Khosla
mesh_terms: D004220:Disulfides / Q000737:chemistry / Q000494:pharmacology*; D004789:Enzyme Activation; D019204:GTP-Binding Proteins / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008856:Microscopy, Fluorescence; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D021241:Spectrometry, Mass, Electrospray Ionization; D013329:Structure-Activity Relationship; D013879:Thioredoxins / Q000037:antagonists & inhibitors*; D011503:Transglutaminases / Q000378:metabolism
chemical_list: D004220:Disulfides; D013879:Thioredoxins; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins