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Selective cellular probes for mammalian thioredoxin reductase TrxR1: rational design of RX1, a modular 1,2-thiaselenane redox probe.
Zeisel, Lukas; Felber, Jan G; Scholzen, Karoline C; Poczka, Lena; Cheff, Dorian; Maier, Martin S; Cheng, Qing; Shen, Min; Hall, Matthew D; Arnér, Elias S J; Thorn-Seshold, Julia; Thorn-Seshold, Oliver.
Afiliación
  • Zeisel L; Department of Pharmacy, Ludwig-Maximilians University of Munich, Butenandtstr. 5-13, 81377 Munich, DE.
  • Felber JG; Department of Pharmacy, Ludwig-Maximilians University of Munich, Butenandtstr. 5-13, 81377 Munich, DE.
  • Scholzen KC; Division of Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Solnavägen 9, 17177 Stock-holm, SE.
  • Poczka L; Department of Pharmacy, Ludwig-Maximilians University of Munich, Butenandtstr. 5-13, 81377 Munich, DE.
  • Cheff D; National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, Maryland 20850, USA.
  • Maier MS; Department of Pharmacy, Ludwig-Maximilians University of Munich, Butenandtstr. 5-13, 81377 Munich, DE.
  • Cheng Q; Division of Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Solnavägen 9, 17177 Stock-holm, SE.
  • Shen M; National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, Maryland 20850, USA.
  • Hall MD; National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, Maryland 20850, USA.
  • Arnér ESJ; Division of Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Solnavägen 9, 17177 Stock-holm, SE.
  • Thorn-Seshold J; Department of Selenoprotein Research, National Institute of Oncology, 1122 Budapest, HU.
  • Thorn-Seshold O; Department of Pharmacy, Ludwig-Maximilians University of Munich, Butenandtstr. 5-13, 81377 Munich, DE.
Chem ; 8(5): 1493-1517, 2022 May 12.
Article en En | MEDLINE | ID: mdl-35936029
Quantifying the activity of key cellular redox players is crucial for understanding physiological homeostasis, and for targeting their perturbed states in pathologies including cancer and inflammatory diseases. However, cellularly-selective probes for oxidoreductase turnover are sorely lacking. We rationally developed the first probes that selectively target the mammalian selenoprotein thioredoxin reductase (TrxR), using a cyclic selenenylsulfide oriented to harness TrxR's unique selenolthiol chemistry while resisting the cellular monothiol background. Lead probe RX1 had excellent TrxR1-selective performance in cells, cross-validated by knockout, selenium starvation, knock-in, and chemical inhibitors. Its background-free fluorogenicity enabled us to perform the first quantitative high-throughput live cell screen for TrxR1 inhibitors, which indicated that tempered SNAr electrophiles may be more selective TrxR drugs than the classical electrophiles used hitherto. The RX1 design thus sets the stage for in vivo imaging of the activity of this key oxidoreductase in health and disease, and can also drive TrxR1-inhibitor drug design.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Chem Año: 2022 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Chem Año: 2022 Tipo del documento: Article Pais de publicación: Estados Unidos