Inhibition of T Cell Receptor Activation by Semi-Synthetic Sesquiterpene Lactone Derivatives and Molecular Modeling of Their Interaction with Glutathione and Tyrosine Kinase ZAP-70

Andrei I. Khlebnikov, Igor A. Schepetkin, Anarkul S. Kishkentaeva, Zhanar R. Shaimerdenova, Gayane A. Atazhanova, Sergazy M. Adekenov, Liliya N. Kirpotina, Mark T. Quinn

Research output: Contribution to journalArticle

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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, 1 β ,10 α -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.

Original languageEnglish
JournalMolecules (Basel, Switzerland)
Volume24
Issue number2
DOIs
Publication statusPublished - 19 Jan 2019

Fingerprint

glutathione
Molecular modeling
Sesquiterpenes
tyrosine
Lactones
T-Cell Antigen Receptor
Protein-Tyrosine Kinases
Glutathione
Chemical activation
activation
Derivatives
methylene
Jurkat Cells
T-cells
interactions
phosphorylation
cysteine
ZAP-70 Protein-Tyrosine Kinase
activity (biology)
thiols

Keywords

  • calcium flux
  • extracellular signal-regulated kinase
  • glutathione
  • molecular modeling
  • sesquiterpene lactones
  • T cell receptor
  • ZAP-70

ASJC Scopus subject areas

  • Analytical Chemistry
  • Chemistry (miscellaneous)
  • Molecular Medicine
  • Pharmaceutical Science
  • Drug Discovery
  • Physical and Theoretical Chemistry
  • Organic Chemistry

Cite this

Inhibition of T Cell Receptor Activation by Semi-Synthetic Sesquiterpene Lactone Derivatives and Molecular Modeling of Their Interaction with Glutathione and Tyrosine Kinase ZAP-70. / Khlebnikov, Andrei I.; Schepetkin, Igor A.; Kishkentaeva, Anarkul S.; Shaimerdenova, Zhanar R.; Atazhanova, Gayane A.; Adekenov, Sergazy M.; Kirpotina, Liliya N.; Quinn, Mark T.

In: Molecules (Basel, Switzerland), Vol. 24, No. 2, 19.01.2019.

Research output: Contribution to journalArticle

Khlebnikov, Andrei I. ; Schepetkin, Igor A. ; Kishkentaeva, Anarkul S. ; Shaimerdenova, Zhanar R. ; Atazhanova, Gayane A. ; Adekenov, Sergazy M. ; Kirpotina, Liliya N. ; Quinn, Mark T. / Inhibition of T Cell Receptor Activation by Semi-Synthetic Sesquiterpene Lactone Derivatives and Molecular Modeling of Their Interaction with Glutathione and Tyrosine Kinase ZAP-70. In: Molecules (Basel, Switzerland). 2019 ; Vol. 24, No. 2.
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AU - Schepetkin, Igor A.

AU - Kishkentaeva, Anarkul S.

AU - Shaimerdenova, Zhanar R.

AU - Atazhanova, Gayane A.

AU - Adekenov, Sergazy M.

AU - Kirpotina, Liliya N.

AU - Quinn, Mark T.

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