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 De Filippis, Usha Viswanathan, John Kulp, Yanming Du, Ju Tao Guo, Jinhong Chang

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

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
Volume5
Issue number7
DOIs
StatePublished - May 6 2019

Fingerprint

Interferons
Genes
Cytokines
Antiviral Agents
Blood Cells
Fibroblasts
High-Throughput Screening Assays
Flavivirus
Interferon Type I
Adaptive Immunity
Virus Diseases
Myeloid Cells
Infection
Innate Immunity
Dendritic Cells
Immunity
Membrane Proteins
Viruses
T-Lymphocytes
DNA

Keywords

  • antiviral
  • high-throughput assay
  • innate immunity
  • STING

ASJC Scopus subject areas

  • Infectious Diseases

Cite this

Zhang, X., Liu, B., Tang, L., Su, Q., Hwang, N., Sehgal, M., ... Chang, J. (2019). Discovery and Mechanistic Study of a Novel Human-Stimulator-of-Interferon-Genes Agonist. ACS Infectious Diseases, 5(7), 1139-1149. https://doi.org/10.1021/acsinfecdis.9b00010

Discovery and Mechanistic Study of a Novel Human-Stimulator-of-Interferon-Genes Agonist. / Zhang, Xiaohui; Liu, Bowei; Tang, Liudi; Su, Qing; Hwang, Nicky; Sehgal, Mohit; Cheng, Junjun; Ma, Julia; Zhang, Xuexiang; Tan, Yinfei; Zhou, Yan; Duan, Zhongping; De Filippis, Victor; Viswanathan, Usha; Kulp, John; Du, Yanming; Guo, Ju Tao; Chang, Jinhong.

In: ACS Infectious Diseases, Vol. 5, No. 7, 06.05.2019, p. 1139-1149.

Research output: Contribution to journalArticle

Zhang, X, Liu, B, Tang, L, Su, Q, Hwang, N, Sehgal, M, Cheng, J, Ma, J, Zhang, X, Tan, Y, Zhou, Y, Duan, Z, De Filippis, V, Viswanathan, U, Kulp, J, Du, Y, Guo, JT & Chang, J 2019, 'Discovery and Mechanistic Study of a Novel Human-Stimulator-of-Interferon-Genes Agonist', ACS Infectious Diseases, vol. 5, no. 7, pp. 1139-1149. https://doi.org/10.1021/acsinfecdis.9b00010
Zhang, Xiaohui ; Liu, Bowei ; Tang, Liudi ; Su, Qing ; Hwang, Nicky ; Sehgal, Mohit ; Cheng, Junjun ; Ma, Julia ; Zhang, Xuexiang ; Tan, Yinfei ; Zhou, Yan ; Duan, Zhongping ; De Filippis, Victor ; Viswanathan, Usha ; Kulp, John ; Du, Yanming ; Guo, Ju Tao ; Chang, Jinhong. / Discovery and Mechanistic Study of a Novel Human-Stimulator-of-Interferon-Genes Agonist. In: ACS Infectious Diseases. 2019 ; Vol. 5, No. 7. pp. 1139-1149.
@article{18761b81b928438f9e86ab5a0e546110,
title = "Discovery and Mechanistic Study of a Novel Human-Stimulator-of-Interferon-Genes Agonist",
abstract = "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.",
keywords = "antiviral, high-throughput assay, innate immunity, STING",
author = "Xiaohui Zhang and Bowei Liu and Liudi Tang and Qing Su and Nicky Hwang and Mohit Sehgal and Junjun Cheng and Julia Ma and Xuexiang Zhang and Yinfei Tan and Yan Zhou and Zhongping Duan and {De Filippis}, Victor and Usha Viswanathan and John Kulp and Yanming Du and Guo, {Ju Tao} and Jinhong Chang",
year = "2019",
month = "5",
day = "6",
doi = "10.1021/acsinfecdis.9b00010",
language = "English (US)",
volume = "5",
pages = "1139--1149",
journal = "ACS Infectious Diseases",
issn = "2373-8227",
publisher = "American Chemical Society",
number = "7",

}

TY - JOUR

T1 - Discovery and Mechanistic Study of a Novel Human-Stimulator-of-Interferon-Genes Agonist

AU - Zhang, Xiaohui

AU - Liu, Bowei

AU - Tang, Liudi

AU - Su, Qing

AU - Hwang, Nicky

AU - Sehgal, Mohit

AU - Cheng, Junjun

AU - Ma, Julia

AU - Zhang, Xuexiang

AU - Tan, Yinfei

AU - Zhou, Yan

AU - Duan, Zhongping

AU - De Filippis, Victor

AU - Viswanathan, Usha

AU - Kulp, John

AU - Du, Yanming

AU - Guo, Ju Tao

AU - Chang, Jinhong

PY - 2019/5/6

Y1 - 2019/5/6

N2 - 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.

AB - 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.

KW - antiviral

KW - high-throughput assay

KW - innate immunity

KW - STING

UR - http://www.scopus.com/inward/record.url?scp=85069799306&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85069799306&partnerID=8YFLogxK

U2 - 10.1021/acsinfecdis.9b00010

DO - 10.1021/acsinfecdis.9b00010

M3 - Article

C2 - 31060350

AN - SCOPUS:85069799306

VL - 5

SP - 1139

EP - 1149

JO - ACS Infectious Diseases

JF - ACS Infectious Diseases

SN - 2373-8227

IS - 7

ER -