Selective Inhibition of Extracellular Thioredoxin by Asymmetric Disulfides

被引:54
作者
DiRaimondo, Thomas R. [1 ]
Plugis, Nicholas M. [2 ]
Jin, Xi [2 ]
Khosla, Chaitan [1 ,2 ]
机构
[1] Stanford Univ, Dept Chem Engn, Stanford, CA 94305 USA
[2] Stanford Univ, Dept Chem, Stanford, CA 94305 USA
关键词
TRANSGLUTAMINASE; 2; T-CELLS; SYSTEM; ACTIVATION; MOLECULE; PX-12;
D O I
10.1021/jm301775s
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
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 utracellular 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 IC50 below 0.1 mu M in cell culture and may be appropriate for in vivo use to interrogate the role of extracellular Trx in health and disease.
引用
收藏
页码:1301 / 1310
页数:10
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