Abstract
A variety of natural compounds have been shown to modulate T cell receptor (TCR) activation, including natural sesquiterpene lactones (SLs). In the present studies, we evaluated the biological activity of 11 novel semi-synthetic SLs to determine their ability to modulate TCR activation. Of these compounds, α-epoxyarglabin, cytisinyl epoxyarglabin, 1β,10α-epoxyargolide, and chloroacetate grosheimin inhibited anti-CD3-induced Ca2+ mobilization and extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation in Jurkat T cells. We also found that the active SLs depleted intracellular glutathione (GSH) in Jurkat T cells, supporting their reactivity towards thiol groups. Because the zeta-chain associated tyrosine kinase 70 kDa (ZAP-70) is essential for TCR signaling and contains a tandem SH2 region that is highly enriched with multiple cysteines, we performed molecular docking of natural SLs and their semi-synthetic derivatives into the ZAP-70 binding site. The docking showed that the distance between the carbon atom of the exocyclic methylene group and the sulfur atom in Cys39 of the ZAP-70 tandem SH2 module was 3.04–5.3 Å for active compounds. Furthermore, the natural SLs and their derivatives could be differentiated by their ability to react with the Cys39 SH-group. We suggest that natural and/or semi-synthetic SLs with an α-methylene-γ-lactone moiety can specifically target GSH and the kinase site of ZAP-70 and inhibit the initial phases of TCR activation.
Highlights
T cells play an essential role in inflammatory and adaptive immune responses, and the deregulation of T cell function can contribute to autoimmune disease [e.g., see [1]
We found that the natural sesquiterpene lactones (SLs) arglabin, grosheimin, argracin, parthenolide, and estafiatin found that the natural sesquiterpene lactones (SLs) arglabin, grosheimin, argracin, parthenolide, and inhibitedinhibited
To assess the biological activity of the 11 semi-synthetic SL analogs and a natural analog of argolide, we evaluated their effects on T cell receptor (TCR) activation-induced responses in Jurkat T cells and compared these effects with the previously measured responses of the parent compounds 1–4 [6]
Summary
T cells play an essential role in inflammatory and adaptive immune responses, and the deregulation of T cell function can contribute to autoimmune disease [e.g., see [1]. A number of SL derivatives with greater potency than their natural analogs adverse effects [11]. Artesunate, a semi-synthetic derivative of artemisinin, has analogs have been synthesized [9]. Several semi-synthetic parthenolide by inhibiting the migration of pathogenic T cells to the CNS [12]. Several semi-synthetic derivatives have been developed for their anti-leukemic activity [13,14]. Synthetic parthenolide derivatives have been developed for their anti-leukemic activity [13,14]. TCR activation we[21,22], performed molecularmolecular docking studies studies the three-dimensional of thesecompounds natural compounds their derivatives using theusing three-dimensional structuresstructures of these natural and their and derivatives to exploreto explore possible binding modes with the ZAP-70 tandem. Possible binding modes with the ZAP-70 tandem SH2 module
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