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Title: Identification of Inhibitors of the Association of ZAP-70 with the T Cell Receptor by High-Throughput Screen

ZAP-70 is a critical molecule in the transduction of T cell antigen receptor signaling and the activation of T cells. Upon activation of the T cell antigen receptor, ZAP-70 is recruited to the intracellular ζ-chains of the T cell receptor, where ZAP-70 is activated and colocalized with its substrates. Inhibitors of ZAP-70 could potentially function as treatments for autoimmune diseases or organ transplantation. In this work, we present the design, optimization, and implementation of a screen for inhibitors that would disrupt the interaction between ZAP-70 and the T cell antigen receptor. Finally, the screen is based on a fluorescence polarization assay for peptide binding to ZAP-70.
Authors:
 [1] ;  [2] ;  [1] ;  [1] ;  [1] ;  [2] ;  [3] ;  [4]
  1. Univ. of California, Berkeley, CA (United States). California Inst. of Quantitative Biosciences and Howard Hughes Medical Inst., Dept. of Molecular and Cell Biology and Department of Chemistry
  2. Univ. of California, San Francisco, CA (United States). Small Molecule Discovery Center, Dept. of Pharmaceutical Chemistry
  3. Univ. of California, San Francisco, CA (United States). Rosalind Russell and Ephrain P. Engleman Rheumatology Research Center for Arthritis and Howard Hughes Medical Inst., Dept. of Medicine
  4. Univ. of California, Berkeley, CA (United States). California Inst. of Quantitative Biosciences and Howard Hughes Medical Inst., Dept. of Molecular and Cell Biology and Department of Chemistry; Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Physical Biosciences Division
Publication Date:
Grant/Contract Number:
AC02-05CH11231
Type:
Accepted Manuscript
Journal Name:
SLAS DISCOVERY: Advancing Life Sciences R&D
Additional Journal Information:
Journal Volume: 22; Journal Issue: 3; Journal ID: ISSN 2472-5552
Publisher:
SAGE
Research Org:
Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
Sponsoring Org:
USDOE; National Institutes of Health (NIH)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; T cell; ZAP-70; fluorescence polarization (FP); time-resolved fluorescence resonance energy transfer (TR-FRET); covalent inhibitor; kinase
OSTI Identifier:
1379661

Visperas, Patrick R., Wilson, Christopher G., Winger, Jonathan A., Yan, Qingrong, Lin, Kevin, Arkin, Michelle R., Weiss, Arthur, and Kuriyan, John. Identification of Inhibitors of the Association of ZAP-70 with the T Cell Receptor by High-Throughput Screen. United States: N. p., Web. doi:10.1177/1087057116681407.
Visperas, Patrick R., Wilson, Christopher G., Winger, Jonathan A., Yan, Qingrong, Lin, Kevin, Arkin, Michelle R., Weiss, Arthur, & Kuriyan, John. Identification of Inhibitors of the Association of ZAP-70 with the T Cell Receptor by High-Throughput Screen. United States. doi:10.1177/1087057116681407.
Visperas, Patrick R., Wilson, Christopher G., Winger, Jonathan A., Yan, Qingrong, Lin, Kevin, Arkin, Michelle R., Weiss, Arthur, and Kuriyan, John. 2016. "Identification of Inhibitors of the Association of ZAP-70 with the T Cell Receptor by High-Throughput Screen". United States. doi:10.1177/1087057116681407. https://www.osti.gov/servlets/purl/1379661.
@article{osti_1379661,
title = {Identification of Inhibitors of the Association of ZAP-70 with the T Cell Receptor by High-Throughput Screen},
author = {Visperas, Patrick R. and Wilson, Christopher G. and Winger, Jonathan A. and Yan, Qingrong and Lin, Kevin and Arkin, Michelle R. and Weiss, Arthur and Kuriyan, John},
abstractNote = {ZAP-70 is a critical molecule in the transduction of T cell antigen receptor signaling and the activation of T cells. Upon activation of the T cell antigen receptor, ZAP-70 is recruited to the intracellular ζ-chains of the T cell receptor, where ZAP-70 is activated and colocalized with its substrates. Inhibitors of ZAP-70 could potentially function as treatments for autoimmune diseases or organ transplantation. In this work, we present the design, optimization, and implementation of a screen for inhibitors that would disrupt the interaction between ZAP-70 and the T cell antigen receptor. Finally, the screen is based on a fluorescence polarization assay for peptide binding to ZAP-70.},
doi = {10.1177/1087057116681407},
journal = {SLAS DISCOVERY: Advancing Life Sciences R&D},
number = 3,
volume = 22,
place = {United States},
year = {2016},
month = {12}
}