Targeting a host process as an antiviral approach against dengue virus

Sayce, Andrew C.; Miller, J. F. A. P.; Zitzmann, Nicole

doi:10.1016/j.tim.2010.04.003

Cited by 49 publications

(52 citation statements)

References 56 publications

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“…Furthermore, the lowering of the effective antiviral dose achieved by PERL-mediated drug delivery provides a potentially effective mechanism to reduce cytotoxicity of drugs with greater in vitro potency against DENV than those tested in this study. The use of a mouse ADE model of DENV infection to test antivirals extends previous data (36,38,45) to demonstrate an anti-DENV effect of NB-DNJ in vivo. Although previous studies evaluated DNJ (45) and NN-DNJ (38), we demonstrate here for the first time the antiviral activity of NB-DNJ against DENV in cell lines, primary cells, and an in vivo model.…”

Section: Discussionsupporting

confidence: 65%

“…NB-DNJ was chosen as a model iminosugar for our experiments examining the ability of polyunsaturated ER-targeting liposomes (PERLs) to enhance iminosugar efficacy against DENV because NB-DNJ is clinically licensed, has relatively low cytotoxicity, and allows easy comparison to previous results obtained for HIV-1. Although this drug is a prototype for other iminosugar derivatives that have antiviral activity against DENV (36), to our knowledge, there are currently no published data on the antiviral activity of NB-DNJ against DENV in vitro or in vivo. We show that NB-DNJ delivered as either a free drug or encapsulated in PERLs enhanced survival in the ADE mouse model and that liposome-mediated delivery increased NB-DNJ potency 2,660-fold.…”

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confidence: 99%

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Liposome-Mediated Delivery of Iminosugars Enhances Efficacy against Dengue Virus In Vivo

Miller

Lachica

Sayce

et al. 2012

Antimicrob Agents Chemother

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Section: Discussionsupporting

confidence: 65%

mentioning

confidence: 99%

Liposome-Mediated Delivery of Iminosugars Enhances Efficacy against Dengue Virus In Vivo

Miller

Lachica

Sayce

et al. 2012

Antimicrob Agents Chemother

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“…Viral enzymes, such as viral proteases and polymerases, are attractive drug targets because they are essential for virus replication and are not expressed by noninfected host cells (26)(27)(28). However, recent examples indicate that host proteins can be successful drug targets as well (29)(30)(31). Although we have not formally excluded the possibility that AM404 acts directly on NS4B, we deem it likely that AM404 targets a cellular pathway that DENV needs for efficient replication.…”

mentioning

confidence: 80%

Escape Mutations in NS4B Render Dengue Virus Insensitive to the Antiviral Activity of the Paracetamol Metabolite AM404

Cleef

Overheul

Thomassen

et al. 2016

Antimicrob Agents Chemother

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Despite the enormous disease burden associated with dengue virus infections, a licensed antiviral drug is lacking. Here, we show that the paracetamol (acetaminophen) metabolite AM404 inhibits dengue virus replication. Moreover, we find that mutations in NS4B that were previously found to confer resistance to the antiviral compounds NITD-618 and SDM25N also render dengue virus insensitive to AM404. Our work provides further support for NS4B as a direct or indirect target for antiviral drug development. Dengue virus (DENV) is a major health concern. The virus was initially estimated to cause 50 million to 100 million infections each year (1, 2), but more recent estimates suggest even greater numbers (390 million infections, of which 96 million manifest clinically) (3). Dengue is a mosquito-transmitted infection that was once considered a tropical disease, but the virus is spreading rapidly across the globe and is now endemic in 128 countries, with up to 4 billion people at risk of infection (1, 4-7). No specific drug or licensed vaccine is available for DENV infection, leaving vector control the only option to prevent transmission, although this approach is threatened by the emergence of insecticide resistance (8-10). A specific antiviral therapeutic agent would be an important tool to inhibit virus replication and transmission and to reduce the global burden of DENV.To identify new inhibitors of DENV replication, we screened the NIH Clinical Collection, a library of small molecules with a history of use in humans, using a replicon-based assay in HeLa cells (11). In this DENV serotype 2 (DENV2) (strain New Guinea C [NGC])-based replicon (RepDVPacLuc), the structural genes are replaced by a puromycin resistance gene and a firefly luciferase (FLuc) reporter gene, which can be assessed as a readout for virus replication (11,12). AM404 (PubChem identification no. 6604822) was one of the compounds that, at a concentration of 10 M, reduced FLuc activity in HeLa DENV2 replicon cells by Ͼ50%, relative to the dimethyl sulfoxide (DMSO) control, without affecting cell viability by Ͼ20%. AM404, also known as Narachidonoylphenolamine, is an active metabolite of paracetamol (acetaminophen) (Fig. 1A) and is suggested to be responsible for all or part of its analgesic activity (13,14).To confirm the results from our screen, we analyzed an independent batch of AM404 (Tocris Bioscience; purity, 99.5% by HPLC) for antiviral activity on HeLa DENV2 replicon cells and found that AM404, but not paracetamol, reduced FLuc activity in a dose-dependent manner (50% effective concentration [EC 50 ], 3.6 M [95% confidence interval [CI], 3.0 to 4.2 M]) (Fig. 1B). As expected (15-17), the nucleoside analogue ribavirin (SigmaAldrich), which was used as a positive control, also inhibited virus replication in a dose-dependent manner (EC 50 , 2.2 M [95% CI, 1.8 to 2.6 M]) (Fig. 1B). Importantly, none of the compounds affected cell viability, as assessed by a colorimetric assay for cell metabolic activity (Fig. 1B). We next analyzed whether AM404 al...

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“…9,10,25 Nevertheless, these types of compounds commonly show a low bioavailability, especially for therapeutic uses, the reason why several strategies to overcome this limitation focus on the use of a wide variety of nanocarriers, including liposomes, solid lipid nanoparticles, nanoemulsions and nanocrystals, or polymeric nanoparticles, among others. 26 Liposomal formulations have shown interesting properties in terms of the effective antiviral dose, decreasing the toxic concentrations and enhancing the retention time of the drug in blood circulation (due to pegylation).…”

Section: Antiviral Drugsmentioning

confidence: 99%

“…Deoxynojirimycin and its N-alkylated derivatives (iminosugars) can be effective against DV infection by targeting host cellular factors that are required for viral morphogenesis. 9 Flavonoids, fisetin, quercetin and baicalein, also exhibited anti-dengue virus activities ( Figure 1). 10 The first major success of the sterile insect technique was achieved against Culex quinquefasciatus in Myanmar in 1967 and efforts were being made against Culex quinquefasciatus and Ae.…”

Section: Introductionmentioning

confidence: 99%

Nanobiotechnology Solutions againstAedes aegypti

Islan

Durán

Castro

2016

Journal of the Brazilian Chemical Society

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United Nations Children's Fund (UNICEF)/United Nations Development Programme (UNDP)/ World Bank/World Health Organization (WHO) implemented the Training in Tropical Diseases (TDR) program with excellent results; however, due to current challenges, this active program requires new and innovative solutions. Nowadays, Aedes aegyptis-borne diseases can be added among neglected diseases. Surveillance and control must be considered owing to a great risk of infection with dengue, chikungunya and zika viruses. Although investigations on several vaccines are in progress, new insights in term of development of drugs that evade from resistance are of paramount importance. Nanobiotechnology appears as one of the most innovative strategy in the search of new uses for old pharmaceuticals or in the development of innovative and intelligent nanomedicines for neglected diseases. Liposomes, solid lipid nanoparticles, nanoemulsions, polymeric nanoparticles, metallic nanoparticles, quantum dots, carbon dots and carbon nanotubes were the focus of the current advances. In this direction, we have focused this overview on new advances in diagnostic assays as nanobiosensors, antivirus and nanoinsecticides on Aedes aegyptis control.

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Targeting a host process as an antiviral approach against dengue virus

Cited by 49 publications

References 56 publications

Liposome-Mediated Delivery of Iminosugars Enhances Efficacy against Dengue Virus In Vivo

Liposome-Mediated Delivery of Iminosugars Enhances Efficacy against Dengue Virus In Vivo

Escape Mutations in NS4B Render Dengue Virus Insensitive to the Antiviral Activity of the Paracetamol Metabolite AM404

Nanobiotechnology Solutions againstAedes aegypti

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