Optimizing celgosivir therapy in mouse models of dengue virus infection of serotypes 1 and 2: The search for a window for potential therapeutic efficacy

Watanabe, Sumio; Chan, Kitti Wing Ki; Dow, Geoffrey S.; Ooi, Eng Eong; Low, Jenny Guek Hong; Vasudevan, Subhash G.

doi:10.1016/j.antiviral.2015.12.008

Cited by 61 publications

(62 citation statements)

References 27 publications

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“…Our follow-up preclinical study reveals the challenges in lowering viral load when drug treatment is initiated near peak viremia, comparable to how most patients present clinically (11). Since severe dengue usually develops after resolution of the viremic phase (28), an alternative endpoint that is directly associated with disease severity is desirable for assessing antiviral drug efficacy.…”

Section: F-fdg Uptake Is Effectively Suppressed With Antiviral Therapmentioning

confidence: 92%

“…Mice were treated with celgosivir 4 times daily (q.i.d. ; 50 mg/kg), following the regimen that has been shown to improve celgosivir efficacy in mice (11) (Figure 2A). The treatment completely protected mice from lethal infection with S221 when dosing commenced on day 2 after infection ( Figure 2B).…”

Section: F-fdg Uptake Is Effectively Suppressed With Antiviral Therapmentioning

confidence: 99%

“…The DENV2 S221 lethal infection model was used for initial validation of 18 F-FDG uptake because of the previous demonstration that focal inflammation and increased viral load in the intestinal region are the principal contributors to the pathology and ultimate lethality (20). Next, we wanted to determine if 18 F-FDG uptake was sufficiently sensitive as a biomarker to distinguish between nonlethal primary (virus alone, Figure 3A) and lethal antibody-enhanced infection (ADE infection, Figure 3B) using a clinical strain of DENV2 (DENV2-3295 [EDEN2]), as we described previously in the AG129 mouse model (11,29). Examination of the kinetics of viral load in the serum ( Figure 3C) revealed no difference in RNA genome equivalent copies between nonlethal infection versus lethal ADE infection with EDEN2 DENV2.…”

Section: F-fdg Uptake Is Effectively Suppressed With Antiviral Therapmentioning

confidence: 99%

“…Serum viral load (viremia), the current clinical diagnostic gold standard, does not always correlate with disease severity, nor does it robustly inform to anti-dengue therapy response under strict clinical trial conditions (10)(11)(12). However, DENV infection is consistently associated with cells of the mononuclear phagocyte lineage, and their increased proinflammatory cytokine production is believed to enhance disease severity by disrupting the integrity of vascular endothelial lining and causing increased vascular permeability (13,14).…”

Section: Introductionmentioning

confidence: 99%

“…Consequently, the mice were treated with anti-TNF antibody, after which they achieved a 100% recovery (20). Furthermore, several examples of nonlethal (virus-only) or lethal ADE infection of AG129 mice with clinical isolates of DENV have been reported, which share disease features that center around inflammation (11,18,19,21). Viremia did not necessarily correlate with disease severity in many of these models (22), and the viral inoculum used in these infection studies also varied.…”

Section: Introductionmentioning

confidence: 99%

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18F-FDG as an inflammation biomarker for imaging dengue virus infection and treatment response

Chacko¹,

Watanabe

Herr³

et al. 2017

JCI Insight

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Section: F-fdg Uptake Is Effectively Suppressed With Antiviral Therapmentioning

confidence: 92%

Section: F-fdg Uptake Is Effectively Suppressed With Antiviral Therapmentioning

confidence: 99%

Section: F-fdg Uptake Is Effectively Suppressed With Antiviral Therapmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

18F-FDG as an inflammation biomarker for imaging dengue virus infection and treatment response

Chacko¹,

Watanabe

Herr³

et al. 2017

JCI Insight

Self Cite

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Recent Developments in the Synthesis of Polyhydroxylated Indolizidines

Fraňová

Marchalı́n

2022

Eur J Org Chem

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Since their discovery, polyhydroxylated indolizidines have been the focus of attention for both biologists and synthetic chemists. They are classified as iminosugar alkaloids: nitrogenbased carbohydrate mimetics that are potent inhibitors of glycosidases. Many discovered glycosidase inhibitors were found to possess biological activity, and they are therefore considered to be potential therapeutics in the treatment of various diseases such as viral infections, diabetes, or cancer. Not surprisingly, the interest in the preparation of these substances has been enormous. This review presents the latest developments in the synthesis of naturally occurring polyhydroxylated indolizidines and their synthetic enantiomers. In addition, the synthesis of several novel polyhydroxylated indolizidines, which were discovered to have inhibitory activity, is reported.

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Mechanisms of Antiviral Activity of Iminosugars Against Dengue Virus

Miller

Tyrrell

Zitzmann

2018

Advances in Experimental Medicine and Biology

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The antiviral mechanism of action of iminosugars against many enveloped viruses, including dengue virus (DENV), HIV, influenza and hepatitis C virus, is believed to be mediated by inducing misfolding of viral N-linked glycoproteins through inhibition of host endoplasmic reticulum-resident α-glucosidase enzymes. This leads to reduced secretion and/or infectivity of virions and hence lower viral titres, both in vitro and in vivo. Free oligosaccharide analysis from iminosugar-treated cells shows that antiviral activity correlates with production of mono- and tri-glucosylated sugars, indicative of inhibition of ER α-glucosidases. We demonstrate that glucose-mimicking iminosugars inhibit isolated glycoprotein and glycolipid processing enzymes and that this inhibition also occurs in primary cells treated with these drugs. Galactose-mimicking iminosugars that have been tested do not inhibit glycoprotein processing but do inhibit glycolipid processing, and are not antiviral against DENV. By comparison, the antiviral activity of glucose-mimetic iminosugars that inhibit endoplasmic reticulum-resident α-glucosidases, but not glycolipid processing, demonstrates that inhibition of α-glucosidases is responsible for iminosugar antiviral activity against DENV. This monograph will review the investigations of many researchers into the mechanisms of action of iminosugars and the contribution of our current understanding of these mechanisms for optimising clinical delivery of iminosugars. The effects of iminosugars on enzymes other than glucosidases, the induction of ER stress and viral receptors will be also put into context. Data suggest that inhibition of α-glucosidases results in inhibited release of virus and is the primary antiviral mechanism of action of iminosugars against DENV.

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Optimizing celgosivir therapy in mouse models of dengue virus infection of serotypes 1 and 2: The search for a window for potential therapeutic efficacy

Cited by 61 publications

References 27 publications

18F-FDG as an inflammation biomarker for imaging dengue virus infection and treatment response

18F-FDG as an inflammation biomarker for imaging dengue virus infection and treatment response

Recent Developments in the Synthesis of Polyhydroxylated Indolizidines

Mechanisms of Antiviral Activity of Iminosugars Against Dengue Virus

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