SB 9200, a novel agonist of innate immunity, shows potent antiviral activity against resistant HCV variants

Jones, Meleri; Cunningham, Morven; Wing, Peter A C; DeSilva, S.; Challa, Rupa; Sheri, Anjaneyulu; Padmanabhan, Seetharamaiyer; Iyer, Radhakrishnan P.; Korba, Brent E.; Afdhal, Nezam H.; Foster, Graham R.

doi:10.1002/jmv.24809

Cited by 25 publications

(24 citation statements)

References 30 publications

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“…These drugs, however, may cause side effects such as lactic acidosis and possible liver, and kidney failure. SB9200 is effective for HCV patients with relapse after DAA and interferon treatment and could serve as a promising treatment option for patients who are not responding to the current regimen of DAA therapy ( 52 ). The phase 1 clinical trial on naïve adult with chronic hepatitis C showed an association between the decline in viral RNA and the peak of SB9200 detection in plasma (Clinical trial no NCT01803308).…”

Section: Nucleotide-based Antiviralsmentioning

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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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: Nucleotide-based Antiviralsmentioning

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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“… 83 , 84 Indeed, the antiviral SB 9200, a novel first-in-class oral modulator of innate immunity with a broad-spectrum activity in vitro and in vivo against RNA viruses including hepatitis C virus, norovirus, respiratory syncytial virus and hepatitis B virus, is also believed to act via NOD2 pathway. 85 Furthermore, infection with human cytomegalovirus results in significant induction of NOD2 expression, activating downstream NF-κB and IFN pathways. 84 Besides, following recognition of a viral ssRNA genome, NOD2 uses the adaptor mitochondrial antiviral signaling protein to activate IRF3; interestingly, NOD2-deficient mice fail to produce IFN efficiently.…”

Section: Introductionmentioning

confidence: 99%

NOD2 and inflammation: current insights

Negroni

Pierdomenico

Cucchiara

et al. 2018

JIR

143

124

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The nucleotide-binding oligomerization domain (NOD) protein, NOD2, belonging to the intracellular NOD-like receptor family, detects conserved motifs in bacterial peptidoglycan and promotes their clearance through activation of a proinflammatory transcriptional program and other innate immune pathways, including autophagy and endoplasmic reticulum stress. An inactive form due to mutations or a constitutive high expression of NOD2 is associated with several inflammatory diseases, suggesting that balanced NOD2 signaling is critical for the maintenance of immune homeostasis. In this review, we discuss recent developments about the pathway and mechanisms of regulation of NOD2 and illustrate the principal functions of the gene, with particular emphasis on its central role in maintaining the equilibrium between intestinal microbiota and host immune responses to control inflammation. Furthermore, we survey recent studies illustrating the role of NOD2 in several inflammatory diseases, in particular, inflammatory bowel disease, of which it is the main susceptibility gene.

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“…A pre-clinical compound specific for RIG-I is RGT100 (Merck/Rigontec), currently in phase I clinical trials for treatment of advanced solid tumors and lymphomas (NCT03065023), although peer-reviewed preclinical reports for RGT100 were not identified, to our knowledge. Another compound which activates RIG-I by unknown mechanisms is SB-9200 [ 78 ], which is currently under investigation as an anti-viral agent, but has not yet been tested in the pre-clinical setting of cancer treatment.…”

Section: Introductionmentioning

confidence: 99%

Harnessing RIG-I and intrinsic immunity in the tumor microenvironment for therapeutic cancer treatment

Elion

Cook

2018

Oncotarget

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Cancer immunotherapies that remove checkpoint restraints on adaptive immunity are gaining clinical momentum. Approaches aimed at intrinsic cellular immunity in the tumor microenvironment are less understood, but are of intense interest, based on their ability to induce tumor cell apoptosis while orchestrating innate and adaptive immune responses against tumor antigens. The intrinsic immune response is initiated by ancient, highly conserved intracellular proteins that detect viral infection. For example, the RIG-I-like receptors (RLRs), a family of related RNA helicases, detect viral oligonucleotide patterns of certain RNA viruses. RLR activation induces immunogenic cell death of virally infected cells, accompanied by increased inflammatory cytokine production, antigen presentation, and antigen-directed immunity against virus antigens. Approaches aimed at non-infectious RIG-I activation in cancers are being tested as a treatment option, with the goal of inducing immunogenic tumor cell death, stimulating production of pro-inflammatory cytokines, enhancing tumor neoantigen presentation, and potently increasing cytotoxic activity of tumor infiltrating lymphocytes. These studies are finding success in several pre-clinical models, and are entering early phases of clinical trial. Here, we review pre-clinical studies of RLR agonists, including the successes and challenges currently faced RLR agonists on the path to clinical translation.

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SB 9200, a novel agonist of innate immunity, shows potent antiviral activity against resistant HCV variants

Cited by 25 publications

References 30 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

NOD2 and inflammation: current insights

Harnessing RIG-I and intrinsic immunity in the tumor microenvironment for therapeutic cancer treatment

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