A small-molecule IRF3 agonist functions as an influenza vaccine adjuvant by modulating the antiviral immune response

Probst, Peter; Grigg, John B.; Wang, Myra; Muñoz, Ernesto J.; Loo, Yueh–Ming; Ireton, Reneé C.; Gale, Michael; Iadonato, Shawn P.; Bedard, Kristin

doi:10.1016/j.vaccine.2017.01.053

Cited by 34 publications

(29 citation statements)

References 19 publications

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“…The therapeutic and prophylactic use of pan-antivirals was previously demonstrated in viral infection of influenza and dengue ( 55 , 69 , 71 ). Hotz et al demonstrated that the pre-exposure of murine APC to synthetic poly(I:C) inhibits RLR activation while augmenting the sensitivity of TLRs.…”

Section: The Danger Of Uncontrolled Immune Activation Always Existsmentioning

confidence: 99%

“…Immunization with vaccine and KIN 1148 showed a significant increase in IgG antibodies with serum from mice receiving prime-boost immunization conferring protection to naïve mice from influenza challenge. KIN1148 was shown to be able to work alongside the vaccine to boost protective immunity and protect against influenza strain A/California/04/2009 (Table 2 ) ( 69 ).…”

Section: Innate Immune Potentiator As Vaccine Adjuvantsmentioning

confidence: 99%

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RIG-I-Like Receptors as Novel Targets for Pan-Antivirals and Vaccine Adjuvants Against Emerging and Re-Emerging Viral Infections

Yong

Luo

2018

Front. Immunol.

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Emerging and re-emerging viruses pose a significant public health challenge around the world, among which RNA viruses are the cause of many major outbreaks of infectious diseases. As one of the early lines of defense in the human immune system, RIG-I-like receptors (RLRs) play an important role as sentinels to thwart the progression of virus infection. The activation of RLRs leads to an antiviral state in the host cells, which triggers the adaptive arm of immunity and ultimately the clearance of viral infections. Hence, RLRs are promising targets for the development of pan-antivirals and vaccine adjuvants. Here, we discuss the opportunities and challenges of developing RLR agonists into antiviral therapeutic agents and vaccine adjuvants against a broad range of viruses.

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Section: The Danger Of Uncontrolled Immune Activation Always Existsmentioning

confidence: 99%

Section: Innate Immune Potentiator As Vaccine Adjuvantsmentioning

confidence: 99%

RIG-I-Like Receptors as Novel Targets for Pan-Antivirals and Vaccine Adjuvants Against Emerging and Re-Emerging Viral Infections

Yong

Luo

2018

Front. Immunol.

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“…Using cells and mice expressing a RIPA active nt-IRF3 mutant, we demonstrated the relative contribution of RIPA to the antiviral response of IRF3 [7]. Several high throughput screens have revealed small molecules that regulate the transcriptional activity of IRF3 [39][40][41][42][43]. However, because RIPA is newly identified, there are no known regulators of this pathway.…”

Section: Discussionmentioning

confidence: 99%

High Throughput Screening of FDA-Approved Drug Library Reveals the Compounds that Promote IRF3-Mediated Pro-Apoptotic Pathway Inhibit Virus Replication

Glanz

Chawla

Fabry

et al. 2020

Viruses

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Interferon (IFN) regulatory factor 3 (IRF3) is the key transcription factor for the induction of IFN and antiviral genes. The absence of antiviral genes in IRF3 deficiency leads to susceptibility to a wide range of viral infections. Previously, we uncovered a function for nontranscriptional IRF3 (nt-IRF3), RLR (RIG-I-like receptor)-induced IRF3-mediated pathway of apoptosis (RIPA), which triggers apoptotic killing of virus-infected cells. Using knock-in mice expressing a transcriptionally inactive, but RIPA-active, IRF3 mutant, we demonstrated the relative contribution of RIPA to host antiviral defense. Given that RIPA is a cellular antiviral pathway, we hypothesized that small molecules that promote RIPA in virus-infected cells would act as antiviral agents. To test this, we conducted a high throughput screen of a library of FDA-approved drugs to identify novel RIPA activators. Our screen identified doxorubicin as a potent RIPA-activating agent. In support of our hypothesis, doxorubicin inhibited the replication of vesicular stomatitis virus, a model rhabdovirus, and its antiviral activity depended on its ability to activate IRF3 in RIPA. Surprisingly, doxorubicin inhibited the transcriptional activity of IRF3. The antiviral activity of doxorubicin was expanded to flavivirus and herpesvirus that also activate IRF3. Mechanistically, doxorubicin promoted RIPA by activating the extracellular signal-regulated kinase (ERK) signaling pathway. Finally, we validated these results using another RIPA-activating compound, pyrvinium pamoate, which showed a similar antiviral effect without affecting the transcriptional activity of IRF3. Therefore, we demonstrate that the RIPA branch of IRF3 can be targeted therapeutically to prevent virus infection.

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“…KIN1148 also induced an influenza virusspecific IL-10 and Th2 response by T cells in the lymph nodes ( Figure 18). [92] AKT Inhibitors…”

Section: Irf3 Agonistsmentioning

confidence: 99%

Benzothiazoles as potential antiviral agents

Asiri

Alsayari

Muhsinah

et al. 2020

Journal of Pharmacy and Pharmacology

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Objectives The recent viral pandemic poses a unique challenge for healthcare providers. Despite the remarkable progress, the number of novel antiviral agents in the pipeline is woefully inadequate against the evolving virulence and drug resistance of current viruses. This highlights the urgent need for new and improved vaccines, diagnostics and therapeutic agents to obviate the viral pandemic. Key findings Benzothiazole plays a pivotal role in the design and development of antiviral drugs. This is evident from the fact that it comprises many clinically useful agents. The current review is aimed to provide an insight into the recent development of benzothiazole-based antiviral agents, with a special focus on their structure-activity relationships and lead optimisation. One hundred and five articles were initially identified, and from these studies, 64 potential novel lead molecules and main findings were highlighted in this review. Summary We hope this review will provide a logical perspective on the importance of improving the future designs of novel broad-spectrum benzothiazolebased antiviral agents to be used against emerging viral diseases. Benzothiazoles as antiviral agents Yahya I. Asiri et al.

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A small-molecule IRF3 agonist functions as an influenza vaccine adjuvant by modulating the antiviral immune response

Cited by 34 publications

References 19 publications

RIG-I-Like Receptors as Novel Targets for Pan-Antivirals and Vaccine Adjuvants Against Emerging and Re-Emerging Viral Infections

RIG-I-Like Receptors as Novel Targets for Pan-Antivirals and Vaccine Adjuvants Against Emerging and Re-Emerging Viral Infections

High Throughput Screening of FDA-Approved Drug Library Reveals the Compounds that Promote IRF3-Mediated Pro-Apoptotic Pathway Inhibit Virus Replication

Benzothiazoles as potential antiviral agents

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