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Gold compounds have a long history of use as immunosuppressants, but their precise mechanism of action is not completely understood. Using our recently developed liver-on-a-chip platform we now show that gold compounds containing planar N-heterocyclic carbene (NHC) ligands are potent ligands for the aryl hydrocarbon receptor (AHR). Further studies showed that the lead compound (MC3) activates TGFβ1 signaling and suppresses CD4+ T-cell activation in vitro, in human and mouse T cells. Conversely, genetic knockdown or chemical inhibition of AHR activity or of TGFβ1-SMAD-mediated signaling offsets the MC3-mediated immunosuppression. In scurfy mice, a mouse model of human immunodysregulation polyendocrinopathy enteropathy X-linked syndrome, MC3 treatment reduced autoimmune phenotypes and extended lifespan from 24 to 58 days. Our findings suggest that the immunosuppressive activity of gold compounds can be improved by introducing planar NHC ligands to activate the AHR-associated immunosuppressive pathway, thus expanding their potential clinical application for autoimmune diseases., Cheng, Haeberle et al. identify NHC–gold complexes as ligands of the aryl hydrocarbon receptor, which triggers TGFβ production for immune suppression. They find that the MC3 compound activates TGFβ signalling while reducing Il-2 expression and CD4+ T-cell activation and suppresses autoimmune phenotypes in a mouse model of IPEX syndrome.

A new liquid chromatography tandem mass spectrometric method for simultaneous estimation of anti-hyperglycemic agents, metformin, linagliptin, sitagliptin and vildagliptin from human plasma was developed and validated as per ICH/USFDA guidelines. Chromatographic separations were achieved using Chromolith® High Resolution RP-18e HPLC column (100 mm × 4.6 mm, macropores 1.15 μm) with an isocratic elution mode using the mobile phase composed of 0.01 M ammonium formate buffer (pH 3.0): acetonitrile (80:20 v/v). A flow rate of 0.4 mL min−1 was maintained throughout the analysis. Detection was performed by triple quadrupole MS fitted with ESI probe functioning in the positive ion MRM mode. Extractions of all the drugs from plasma were carried out by acetonitrile crash technique. Alogliptin was used as an internal standard to minimize the error which could occur during analysis. The validation study data demonstrated that the new method is highly selective and sensitive (the limits of detection were 1.76, 1.94, 0.17 and 3.08 ng mL−1 for metformin, linagliptin, sitagliptin and vildagliptin, respectively). The %CV and %RE values were within the acceptable limit, 0.999) was obtained at the concentration range of 0.5–400.0; 5.0–400.0; 10.0–500.0 and 0.5–40.0 ng mL−1 for metformin, linagliptin, sitagliptin and vildagliptin, respectively. The extraction efficacy was evidenced from recovery study and all four analytes were found to be stable in plasma. The developed LC–MS/MS method is robust and can be applied for monitoring plasma levels of analyzed antidiabetic drugs in preclinical and clinical pharmacokinetic studies.

The global spread of the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) has called for an urgent need for dedicated antiviral therapeutics. Metal complexes are commonly underrepresented in compound libraries that are used for screening in drug discovery campaigns, however, there is growing evidence for their role in medicinal chemistry. Based on previous results, we have selected more than 100 structurally diverse metal complexes for profiling as inhibitors of two relevant SARS‐CoV‐2 replication mechanisms, namely the interaction of the spike (S) protein with the ACE2 receptor and the papain‐like protease PLpro. In addition to many well‐established types of mononuclear experimental metallodrugs, the pool of compounds tested was extended to approved metal‐based therapeutics such as silver sulfadiazine and thiomersal, as well as polyoxometalates (POMs). Among the mononuclear metal complexes, only a small number of active inhibitors of the S/ACE2 interaction was identified, with titanocene dichloride as the only strong inhibitor. However, among the gold and silver containing complexes many turned out to be very potent inhibitors of PLpro activity. Highly promising activity against both targets was noted for many POMs. Selected complexes were evaluated in antiviral SARS‐CoV‐2 assays confirming activity for gold complexes with N‐heterocyclic carbene (NHC) or dithiocarbamato ligands, a silver NHC complex, titanocene dichloride as well as a POM compound. These studies might provide starting points for the design of metal‐based SARS‐CoV‐2 antiviral agents., Despite their increasing relevance in medicinal chemistry, metal complexes are still underrepresented in compound screening libraries for drug discovery. In this work more than 100 metal complexes were evaluated as inhibitors of two targets in the SARS‐CoV‐2 life cycle, the interaction of the spike protein with the ACE2 receptor and the protease PLpro. The most active inhibitors were studied for antiviral effects in SARS‐CoV‐2 infected cells and led to the discovery of active compounds that will provide starting points for future drug design.