- Selective inhibition of extracellular thioredoxin by asymmetric disulfides
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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.
- Diraimondo, Thomas R.,Plugis, Nicholas M.,Jin, Xi,Khosla, Chaitan
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- Cyclohexyl-containing asymmetric disulfide compounds and application thereof in preparation of antibacterial drugs
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The invention relates to cyclohexyl-containing asymmetric disulfide compounds and an application thereof in preparation of antibacterial drugs. The cyclohexyl-containing asymmetric disulfide compounds have a strong inhibition effect on MRSA (methicillin-resistant Staphylococcus aureus), staphylococcus aureus and Candida albicans and can be used for preparing the novel antibacterial drugs. The drugs can be prepared into forms of injections, tablets, pills, capsules, suspending agents or emulsions for use. Administration routes of the drugs can be oral administration, percutaneous administration and intravenous or intramuscular injection.
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Paragraph 0017; 0018
(2017/01/12)
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