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, Yan Zhou, Zhongping Duan, Victor R. Defilippis, Usha Viswanathan, John Kulp, Yanming Du, Ju Tao Guo, Jinhong Chang

Research output: Contribution to journalArticlepeer-review

43 Scopus citations


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-N-(naphthalen-1-yl)benzo[d][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.

Original languageEnglish (US)
Pages (from-to)1139-1149
Number of pages11
JournalACS Infectious Diseases
Issue number7
StatePublished - May 6 2019


  • antiviral
  • high-throughput assay
  • innate immunity

ASJC Scopus subject areas

  • Infectious Diseases


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