Antiviral activity of geneticin against dengue virus

Zhang, Xianchao G.; Mason, Peter W.; Dubovi, Edward J.; Xu, Xiaodong; Bourne, Nigel; Renshaw, Randall W.; Block, Timothy M.; Birk, Alexander

doi:10.1016/j.antiviral.2009.02.204

Cited by 48 publications

(35 citation statements)

References 37 publications

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“…Two other drugs, Tirofiban and Eptifibatide, were designed based on snake venom components and are available in the market as antiplatelet agents [16], [17]. In addition, snake venoms and their components have shown antiviral activity against Measles virus [18], Sendai virus [19], Dengue virus [20], [21], and Human immunodeficiency virus (HIV) [22]. One of the main components of snake venom is secreted phospholipase A 2 (sPLA 2 ), which has shown systemic toxicities that include myotoxicity, cardiotoxicity, neurotoxicity, nephrotoxicity, hepatotoxicity, reprotoxicity, and systemic hemorrhage [23]–[28].…”

Section: Introductionmentioning

confidence: 99%

Phospholipase A2 Isolated from the Venom of Crotalus durissus terrificus Inactivates Dengue virus and Other Enveloped Viruses by Disrupting the Viral Envelope

et al. 2014

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The Flaviviridae family includes several virus pathogens associated with human diseases worldwide. Within this family, Dengue virus is the most serious threat to public health, especially in tropical and sub-tropical regions of the world. Currently, there are no vaccines or specific antiviral drugs against Dengue virus or against most of the viruses of this family. Therefore, the development of vaccines and the discovery of therapeutic compounds against the medically most important flaviviruses remain a global public health priority. We previously showed that phospholipase A2 isolated from the venom of Crotalus durissus terrificus was able to inhibit Dengue virus and Yellow fever virus infection in Vero cells. Here, we present evidence that phospholipase A2 has a direct effect on Dengue virus particles, inducing a partial exposure of genomic RNA, which strongly suggests inhibition via the cleavage of glycerophospholipids at the virus lipid bilayer envelope. This cleavage might induce a disruption of the lipid bilayer that causes a destabilization of the E proteins on the virus surface, resulting in inactivation. We show by computational analysis that phospholipase A2 might gain access to the Dengue virus lipid bilayer through the pores found on each of the twenty 3-fold vertices of the E protein shell on the virus surface. In addition, phospholipase A2 is able to inactivate other enveloped viruses, highlighting its potential as a natural product lead for developing broad-spectrum antiviral drugs.

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Section: Introductionmentioning

confidence: 99%

Phospholipase A2 Isolated from the Venom of Crotalus durissus terrificus Inactivates Dengue virus and Other Enveloped Viruses by Disrupting the Viral Envelope

et al. 2014

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“…Over the past 30 years, infection with DENV has emerged as one of the most significant health risks in tropical and subtropical regions worldwide, with upward of 50 million people infected yearly. 3 Further, according to the World Health Organization, two-6-O-butanoyl castanospermine, 9 Geneticin, 10 and an adenosine analog NITD008. 11 However, only few of these compounds appear to have the pharmacologic properties appropriate for a commercial drug and no drug against DENV has yet shown efficacy in a clinical trial.…”

Section: Introductionmentioning

confidence: 99%

High-Content Assay to Identify Inhibitors of Dengue Virus Infection

Shum

Smith

Hirsch

et al. 2010

ASSAY and Drug Development Technologies

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Dengue virus (DENV) infections are vectored by mosquitoes and constitute one of the most prevalent infectious diseases in many parts of the world, affecting millions of people annually. Current treatments for DENV infections are nonspecific and largely ineffective. In this study, we describe the adaptation of a high-content cell-based assay for screening against DENV-infected cells to identify inhibitors and modulators of DENV infection. Using this high-content approach, we monitored the inhibition of test compounds on DENV protein production by means of immunofluorescence staining of DENV glycoprotein envelope, simultaneously evaluating cytotoxicity in HEK293 cells. The adapted 384-well microtiter-based assay was validated using a small panel of compounds previously reported as having inhibitory activity against DENV infections of cell cultures, including compounds with antiviral activity (ribavirin), inhibitors of cellular signaling pathways (U0126), and polysaccharides that are presumed to interfere with virus attachment (carrageenan). A screen was performed against a collection of 5,632 well-characterized bioactives, including U.S. Food and Drug Administration-approved drugs. Assay control statistics show an average Z' of 0.63, indicative of a robust assay in this cell-based format. Using a threshold of >80% DENV inhibition with <20% cellular cytotoxicity, 79 compounds were initially scored as positive hits. A follow-up screen confirmed 73 compounds with IC 50 potencies ranging from 60 nM to 9 mM and yielding a hit rate of 1.3%. Over half of the confirmed hits are known to target transporters, receptors, and protein kinases, providing potential opportunity for drug repurposing to treat DENV infections. In summary, this assay offers the opportunity to screen libraries of chemical compounds, in an effort to identify and develop novel drug candidates against DENV infections.

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“…N-nonyl-deoxynojirimycin, an iminosugar derivative similar to castanospermine, was also effective in reducing disease parameters in an AG129 model [20]. Geneticin is an aminoglycoside that has shown activity against DENV in cell culture, but is inactive against YFV [142]. In the same study, other aminoglycosides, including gentamicin, kanamycin and a guanidinylated geneticin, showed no activity against DENV.…”

Section: Other Host Cell Targetsmentioning

confidence: 89%

Important Advances in the Field of Anti-Dengue Virus Research

Julander

Perry

Shresta

2011

Antivir Chem Chemother

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There are currently no licensed antivirals available for the treatment of dengue virus (DENV), which causes significant morbidity and mortality throughout tropical areas of the world and is now encroaching on the southern United States. Recent improvements in existing animal models and cell culture systems have been very important in elucidating the mechanisms of DENV pathogenesis in humans, including the identification of potential viral and host proteins that might be targeted for the treatment of DENV infection. The AG129 mouse model is a major advance in the development of antiviral and vaccine candidates for clinical use. It allows for testing of potential therapeutics in a relevant system that exhibits some aspects of disease that are similar to those observed in humans. This review focuses on recent developments in the AG129 mouse model and discusses compounds that have been found to be active in available cell and animal model systems within the past year.

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Antiviral activity of geneticin against dengue virus

Cited by 48 publications

References 37 publications

Phospholipase A2 Isolated from the Venom of Crotalus durissus terrificus Inactivates Dengue virus and Other Enveloped Viruses by Disrupting the Viral Envelope

Phospholipase A2 Isolated from the Venom of Crotalus durissus terrificus Inactivates Dengue virus and Other Enveloped Viruses by Disrupting the Viral Envelope

High-Content Assay to Identify Inhibitors of Dengue Virus Infection

Important Advances in the Field of Anti-Dengue Virus Research

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