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Discovery and Mechanistic Study of a Novel Human-Stimulator-of-Interferon-Genes Agonist
Journal article   Open access

Discovery and Mechanistic Study of a Novel Human-Stimulator-of-Interferon-Genes Agonist

Xiaohui Zhang, Bowei Liu, Liudi Tang, Qing Su, Nicky Hwang, Mohit Sehgal, Junjun Cheng, Julia Ma, Xuexiang Zhang, Yinfei Tan, …
ACS infectious diseases, v 5(7), pp 1139-1149
12 Jul 2019
DOI: https://doi.org/10.1021/acsinfecdis.9b00010
PMID: 31060350
Featured in Collection :   UN Sustainable Development Goals @ Drexel
url
https://europepmc.org/articles/pmc7082846View
Accepted (AM),  Open

Abstract

Adaptive Immunity - drug effects Antiviral Agents - chemical synthesis Antiviral Agents - chemistry Antiviral Agents - pharmacology Benzodioxoles - chemical synthesis Benzodioxoles - chemistry Benzodioxoles - pharmacology Cells, Cultured Flavivirus Infections - immunology Hep G2 Cells High-Throughput Screening Assays Humans Immunity, Innate - drug effects Interferons - metabolism Membrane Proteins - agonists Membrane Proteins - chemistry Molecular Structure Small Molecule Libraries - chemical synthesis Small Molecule Libraries - chemistry Small Molecule Libraries - pharmacology Structure-Activity Relationship
Stimulator of interferon genes (STING) is an integral ER-membrane protein that can be activated by 2'3'-cGAMP synthesized by cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) upon binding of double-stranded DNA. It activates interferon (IFN) and inflammatory cytokine responses to defend against infection by microorganisms. Pharmacologic activation of STING has been demonstrated to induce an antiviral state and boost antitumor immunity. We previously reported a cell-based high-throughput-screening assay that allowed for identification of small-molecule cGAS-STING-pathway agonists. We report herein a compound, 6-bromo- -(naphthalen-1-yl)benzo[ ][1,3]dioxole-5-carboxamide (BNBC), that induces a proinflammatory cytokine response in a human-STING-dependent manner. Specifically, we showed that BNBC induced type I and III IFN dominant cytokine responses in primary human fibroblasts and peripheral-blood mononuclear cells (PBMCs). BNBC also induced cytokine response in PBMC-derived myeloid dendritic cells and promoted their maturation, suggesting that STING-agonist treatment could potentially regulate the activation of CD4+ and CD8+ T lymphocytes. As anticipated, treatment of primary human fibroblast cells with BNBC induced an antiviral state that inhibited the infection of several kinds of flaviviruses. Taken together, our results indicate that BNBC is a human-STING agonist that not only induces innate antiviral immunity against a broad spectrum of viruses but may also stimulate the activation of adaptive immune responses, which is important for the treatment of chronic viral infections and tumors.

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UN Sustainable Development Goals (SDGs)

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Collaboration types
Domestic collaboration
International collaboration
Web of Science research areas
Chemistry, Medicinal
Infectious Diseases
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