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Accepted (AM)Open Access (License Unspecified), Open
Journal article
A cell-based high throughput screening assay for the discovery of cGAS-STING pathway agonists
Antiviral research, v 147
01 Nov 2017
PMID: 28982551
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Stimulator of interferon genes (STING) is an endoplasmic reticulum transmembrane protein that serves as a molecular hub for activation of interferon and inflammatory cytokine response by multiple cellular DNA sensors. Not surprisingly, STING has been demonstrated to play an important role in host defense against microorganisms and pharmacologic activation of STING is considered as an attractive strategy to treat viral diseases and boost antitumor immunity. In light of this we established a HepAD38-derived reporter cell line that expresses firefly luciferase in response to the activation of cyclic GMP-AMP synthase (cGAS)-STING pathway for high throughput screening (HTS) of small molecular human STING agonists. This cell-based reporter assay required only 4 h treatment with a reference STING agonist to induce a robust luciferase signal and was demonstrated to have an excellent performance in HTS format. By screening 16,000 compounds, a dispiro diketopiperzine (DSDP) compound was identified to induce cytokine response in a manner dependent on the expression of functional human STING, but not mouse STING. Moreover, we showed that DSDP induced an interferon-dominant cytokine response in human skin fibroblasts and peripheral blood mononuclear cells, which in turn potently suppressed the replication of yellow fever virus, dengue virus and Zika virus. We have thus established a robust cell-based assay system suitable for rapid discovery and mechanistic analyses of cGAS-STING pathway agonists. Identification of DSDP as a human STING agonist enriches the pipelines of STING-targeting drug development for treatment of viral infections and cancers.
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Details
- Title
- A cell-based high throughput screening assay for the discovery of cGAS-STING pathway agonists
- Creators
- Bowei Liu - Baruch S. Blumberg InstituteLiudi Tang - Drexel UniversityXiaohui Zhang - Baruch S. Blumberg InstituteJulia Ma - Baruch S. Blumberg InstituteMohit Sehgal - Baruch S. Blumberg InstituteJunjun Cheng - Baruch S. Blumberg InstituteXuexiang Zhang - Baruch S. Blumberg InstituteYan Zhou - Fox Chase Cancer CenterYanming Du - Baruch S. Blumberg InstituteJohn Kulp - Baruch S. Blumberg InstituteJu-Tao Guo - Baruch S. Blumberg InstituteJinhong Chang - Baruch S. Blumberg Institute
- Publication Details
- Antiviral research, v 147
- Publisher
- Elsevier
- Number of pages
- 10
- Grant note
- Commonwealth of Pennsylvania through the Hepatitis B Foundation R01AI113267 / NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Allergy & Infectious Diseases (NIAID) AI113267 / National Institutes of Health, USA; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA Arbutus Biopharma Inc.
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Microbiology and Immunology
- Web of Science ID
- WOS:000416394900005
- Scopus ID
- 2-s2.0-85030481650
- Other Identifier
- 991019167522504721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Pharmacology & Pharmacy
- Virology