bluuebunny/crossref_metadata_2025 huggingface dataset:
High Frequency of Spontaneous Helicase-Primase Inhibitor (BAY 57–1293) Drug-Resistant Variants in Certain Laboratory Isolates of HSV-1
Authors: Biswas Subhajit , Swift Mihaiela , Field Hugh J
Published: March 2015

The authors wish to draw attention to the following errors in their article:

On page 15 an incorrect sequence database was referenced. The sentence ‘A set of eight pairs of overlapping HSV-1-specific primers (designed on the basis of HSV-1 strain 17 sequence; Genbank accession number NC001806) was used (McGeoch et al., 1988).’ should read ‘A set of eight pairs of overlapping HSV-1-specific primers (designed on the basis of HSV-1 strain 17 sequence; RefSeq accession number NC001806) was used (McGeoch et al., 1988).’

On Table 2 an incorrect symbol was used: ‘$reported by Liuzzi et al., 2004’ should be replaced by ‘♠reported by Liuzzi et al., 2004’. A corrected table can be found below.

On Table 3 the 5th column heading is incorrect: ‘BAY 57–1293 concentration, mg/ml’ should read ‘BAY 57–1293 concentration µg/ml’. A corrected table can be found below.

[Table: see text]

[Table: see text]
Effect of Oral Gavage Treatment with ZnAL42 and other Metallo-Ion Formulations on Influenza a H5N1 and H1N1 Virus Infections in Mice
Authors: Barnard Dale L , Wong Min-Hui , Bailey Kevin , Day Craig W , Sidwell Robert W , Hickok Stephen S , Hall Tony J
Published: March 2015

Avian influenza H5N1 infections can cause severe, lethal human infections. Whether influenza A virus treatments effectively ameliorate avian influenza H5N1 human infections is uncertain. The research objective was to evaluate the efficacy of novel zinc and other metallo-ion formulations in two influenza A mouse models. Mice infected with influenza A/Duck/MN/1525/81 (H5N1) virus were treated orally 48 h before virus exposure and then twice daily for 13 days with ZnAL42. The optimal dosing regimen for ZnAL42 was achieved at 17.28 mg/kg 48 h prior to virus exposure, twice daily for 7 days. The survival rate was 80% compared with 10% in the untreated control group and a 100% survival rate with ribavirin (75 mg/kg/day, twice a day for 5 days, beginning 4 h before virus exposure). ZnAL42 treatment significantly lessened the decline in arterial oxygen saturation (SaO2; P<0.001). This regimen was also well tolerated by the mice. Manganese and selenium formulations were not inhibitory to virus replication when given therapeutically. Mice were also infected with influenza A/NWS/33 (H1N1) virus and were treated 48 h before virus exposure with three dosages of ZnAL42 (8.64, 1.46 or 0.24 mg/kg/day). Treatment was by oral gavage twice daily for 13 days. The highest dose of ZnAL42 was significantly inhibitory to the virus infection as seen by prevention of deaths and lessening of decline in SaO2. The data suggest that the prophylactic use of ZnAL42 is effective against avian influenza H5N1 or H1N1 virus infection in mice and should be further explored as an option for treating human influenza virus infections.
In Vitro Pre- and Post-Exposure Prophylaxis Using HIV Inhibitors as Microbicides Against Cell-Free or Cell-Associated HIV-1 Infection
Authors: Terrazas-Aranda Katty , Van Herrewege Yven , Lewi Paul J , Van Roey Jens , Vanham Guido
Published: March 2015

Several classes of microbicides are being evaluated for the prevention of sexual HIV transmission. In vivo, the infectious dose and viral source involved in transmission remain uncertain and it is likely that women will use microbicides both before and after high-risk HIV exposure. Therefore, we evaluated HIV entry inhibitors (EIs) and reverse transcriptase inhibitors (RTIs) for their ability to block cell-free and cell-associated HIV-1 infection in co-cultures of monocyte-derived dendritic cells (MO-DC) and CD4+T-cells using settings of pre- and post-exposure prophylaxis. In the pre-exposure assay, where compound was present before, during and 24 h after infection, all tested EIs (BMS806, TAK779 and T20) and RTIs (PMPA, TMC120 and UC781) blocked infection with 10−4multiplicity of infection (MOI) of cell-free virus at a dose between 100 and 10,000 nM, dependent on the compound used. At 10−3MOI, however, only T20 and the RTIs completely blocked infection. Furthermore, in experiments with cell-associated virus, EIs were ineffective, whereas RTIs actively blocked infection with similar potency as in the experiments with cell-free virus. In the post-exposure assay, where compound was added 2 h after infection and remained present for 24 h, EIs were inactive whereas RTIs blocked cell-free and cell-associated viral infections equally efficiently. Moreover, post-exposure prophylaxis initiated 24 h after infection with cell-free or cell-associated HIV-1 was still effective with 1,000 nM of TMC120. Both EIs and RTIs were non-cytotoxic at any tested concentration for MO-DC and CD4+T-cells in co-culture. Our study shows that RTIs are potent inhibitors of cell-free and cell-associated virus used either in pre- or post-exposure settings. It highlights that parameters such as viral input, viral source, the time of compound addition and the target cells should be considered in microbicides evaluation.
Recent Advances in Our Understanding of Receptor Binding, Viral Fusion and Cell Entry of Hepatitis C Virus: New Targets for the Design of Antiviral Agents
Authors: Poumbourios Pantelis , Drummer Heidi E
Published: March 2015

Improvements to antiviral therapies for the treatment of hepatitis C virus (HCV) infections will require the use of multiple drugs that target viral proteins essential for replication. The discovery of anti-HCV compounds has been severely hampered by the lack of cell culture replication systems. Since the late 1990s, the advent of sub-genomic replicons that model the intracellular events leading to HCV genome replication have enabled the discovery of HCV protease and polymerase inhibitors, but did not allow the study of HCV entry or entry inhibitors. More recently, retroviral pseudotyping of the viral glycoproteins and the development of a cell culture-based system that recapitulates the entire HCV replication cycle were achieved. These new experimental systems have enabled a rapid advance in our knowledge of how HCV glycoproteins, E1 and E2, mediate receptor binding and viral entry. These systems have facilitated the discovery of a range of viral receptors. Evidence is emerging that CD81, scavenger receptor class B type I, claudin-1 and the low-density lipoprotein receptor are involved in viral entry. In addition, DC-SIGN and L-SIGN may function to internalize virus into dendritic or endothelial cells, facilitating the transport of virions to sites of infection such as the liver. This review focuses on the interaction between the HCV glycoproteins and cellular receptors, and our current understanding of the viral entry pathway. In addition, key questions on the role that these receptors play in viral entry are raised and potential avenues for the discovery of new antiviral agents are highlighted.
Potent and Selective Inhibition of Tat-Dependent HIV-1 Replication in Chronically Infected Cells by a Novel Naphthalene Derivative JTK-101
Authors: Wang Xin , Yamataka Kazunobu , Okamoto Mika , Ikeda Satoru , Baba Masanori
Published: March 2015

In search for effective human immunodeficiency virus type 1 (HIV-1) transcription inhibitors, we have evaluated more than 100,000 compounds for their inhibitory effects on HIV-1 long terminal repeat (LTR)-driven reporter gene expression, and identified a novel naphthalene derivative, JTK-101. This compound could suppress tumour necrosis factor (TNF)-α-induced HIV-1 production in latently infected OM-10.1 cells at nanomolar concentrations. JTK-101 could also potently inhibit constitutive HIV-1 production in MOTL-4/IIIB. However, the antiviral activity of JTK-101 was found to be much weaker in acutely infected cells and the chronically infected cells U937/IIIB cells than in OM-10.1 and MOLT-4/IIIB cells. JTK-101 selectively suppressed TNF-α-induced HIV-1 mRNA synthesis in OM-10.1 cells in a dose-dependent fashion. JTK-101 modestly inhibited TNF-α-induced HIV-1 LTR-driven reporter gene expression, but potently inhibited Tat-induced gene expression. Immunoblot analysis revealed that low-level expression of the Tat cofactors CDK9 and cyclin T1 might contribute to the diminished antiviral activity in U937/IIIB cells. Furthermore, JTK-101 could not inhibit HIV-1 replication in chronically infected monocytes/macrophages, in which CDK9 and cyclin T1 were undetectable. These results suggest that JTK-101 exerts its anti-HIV-1 activity through the inhibition of known or unknown Tat cofactors, presumably CDK9/cyclin T1.
Development of a Novel Mouse Model to Evaluate Drug Candidates against Hepatitis B Virus
Authors: Feitelson Mark A , Clayton Marcia M , Sun Bill , Schinazi Raymond F
Published: March 2015

Woodchuck hepatitis virus (WHV)-infected woodchucks have been used for preclinical development of drugs against hepatitis B virus (HBV). However, there is no simple in vivo model to evaluate small amounts of compounds against HBV. To develop such a model, HepAD38 cells, in which HBV replication is regulated by tetracycline (tet), were grown as subcutaneous tumours in nude mice. Mice developing viraemia were then left untreated or given tet in the drinking water. In some of the mice given tet, it was removed and the mice were injected intraperitoneally with phosphate buffer saline (PBS), lamivudine (3TC), clevudine (CLV) or tenofovir dipivoxil fumarate (TDF). Virus DNA titres were measured by real-time PCR during and after drug treatment. In water-fed and PBS-injected mice, virus titres reached ∼109copies/ml serum within 35 days of HepAD38 injection, whereas in tet-treated mice, virus titres remained at 104-105copies/ml. HBV DNA levels were suppressed by 3TC, TDF and CLV, with the latter two drugs showing more sustained virus suppression compared with 3TC. Combination therapy with CLV plus TDF was much more effective than either drug alone in suppressing virus titre for at least 3 weeks after the end of treatment. There was no demonstrable toxicity to HepAD38 cells in drug-treated mice. Hence, a robust tet-controlled system for HBV replication in vivo was demonstrated, validated with monotherapies against HBV and shown to be useful in assessing combination therapy. This system will be useful for preclinical assessment of small amounts of single or multiple compounds against HBV in vivo.
A Comparison of the Phenotypic Susceptibility Profiles of Emtricitabine and Lamivudine
Authors: Borroto-Esoda Katyna , Parkin Neil , Miller Michael D
Published: March 2015

Emtricitabine (FTC) and lamivudine (3TC) are cytosine nucleoside analogues approved for use in HIV-1 infection. Both compounds select for the M184V/I mutation resulting in high-level resistance. This study compared the phenotypic resistance profiles of FTC and 3TC. Both compounds were tested against clinical samples submitted for routine resistance testing (PhenoSense™ HIV assay). We evaluated 306 viruses with nucleoside reverse transcriptase inhibitor mutations (NRTI-R) and 100 viruses without resistance mutations (WT). Seventy-two percent had ≥1 thymidine analogue mutation (TAM), 21% had mixtures at M184, 14% had L74V and 7.5% had K65R. Results were expressed as fold change (FC) in 50% effective concentration compared with the NL4–3 reference. Concordance of FC was evaluated based on biological (99th percentile of the distribution of WT virus population) and clinical cutoffs (FC above which an optimal virological response declines). Against the WT viruses, FTC and 3TC had identical mean FC values relative to the NL4–3 reference of 0.9-fold +0.2 and identical biological cutoffs of 1.4-fold against WT viruses. For NRTI-R isolates, there was a strong linear correlation between FTC and 3TC FC values (r2=0.94). Moreover, there was >90% concordance in resistance calls based on either the biological (1.4-fold) or proposed clinical (3.5-fold) cutoffs among all NRTI-R isolates or isolates with M184V/I mixtures. In the absence of M184V/I, the majority of samples with resistance (>3.5 FC) exhibited TAMs with a trend toward increased levels of cross-resistance with increasing numbers of TAMs. FTC and 3TC demonstrate nearly identical phenotypic resistance profiles and have the same biological cutoff in this panel of NRTI-R and WT clinical HIV-1 isolates.
The Balance between NRTI Discrimination and Excision Drives the Susceptibility of HIV-1 RT Mutants K65R, M184V and K65R+M184V
Authors: Ly John K , Margot Nicolas A , MacArthur Holly L , Hung Magdeleine , Miller Michael D , White Kirsten L
Published: March 2015

The HIV-1 reverse transcriptase (RT) resistance mutations K65R and M184V occur individually and in combination, and can contribute to decreased treatment responses in patients. In order to understand how these mutations interact with one another to confer drug resistance, the susceptibilities and underlying resistance mechanisms of these mutants to nucleoside RT inhibitors (NRTIs) were determined. Virus carrying K65R have reduced susceptibility to most NRTIs, but retain full susceptibility to zidovudine (AZT). M184V mutants have reduced susceptibility to lamivudine (3TC), emtricitabine (FTC) and didanosine (ddI), and contribute to reduced susceptibility to abacavir; however, they remain fully susceptible to tenofovir (TFV), AZT and stavudine (d4T). In cell culture, the K65R+M184V virus showed slightly increased susceptibility to TFV, AZT and d4T compared with K65R alone, but showed further decreases in susceptibility to 3TC, FTC, ddI and abacavir. There are two major biochemical mechanisms of resistance: altered NRTI binding/incorporation and altered NRTI excision after incorporation. For most NRTIs, the primary mechanism of resistance by K65R, M184V and K65R+M184V mutant RTs is to disrupt the NRTI- binding/incorporation steps. In the case of AZT, however, decreased binding/incorporation by K65R and K65R+M184V was counteracted by decreased AZT excision resulting in wild-type susceptibility. For TFV, decreased excision by K65R and K65R+M184V may partially counteract the K65R-driven decrease in incorporation relative to wild-type resulting in only low levels of TFV resistance. The K65R-mediated effect on decreasing NRTI excision was stronger than for M184V. These studies show that both mechanisms of resistance (binding/incorporation and excision) must be considered when defining resistance mechanisms.
Antiviral Chemistry & Chemotherapy's Current Antiviral Agents FactFile (2nd Edition): DNA Viruses
Authors: Field Hugh J , De Clercq Erik
Published: March 2015

Although most of the recent attempts to develop new antiviral agents have been focussed on RNA viruses (in particular, HIV and hepatitis C virus), a few new compounds are now awaiting their entry into the field of DNA viruses, particularly poxviruses, such as variola virus, because of the bioterrorist context, and herpesviruses, such as herpes simplex virus and cytomegalovirus, where the market scene has for many years been dominated by acyclovir, penciclovir and ganciclovir and their respective orally bioavailable prodrugs: valaciclovir, famciclovir and valganciclovir. Here, we review the current ‘state of the art’ with old compounds ready to rotate off and new compounds eagerly awaiting to appear on the continuously evolving scene of antiviral drug development.
Antiviral Chemistry & Chemotherapy's Current Antiviral Agents FactFile 2008 (2nd Edition): RNA Viruses
Authors: De Clercq Erik , Field Hugh J
Published: March 2015

Among the RNA viruses, other than the retroviruses (that is, HIV), which are dealt with separately in the current FactFile, the most important targets for the development of antiviral agents at the moment are the orthomyxoviruses (that is, influenza), the hepaciviruses (that is, hepatitis C virus [HCV]) and, to a lesser extent, the picornaviruses. Although the uncoating inhibitors amantadine and rimantadine were the first known inhibitors of influenza A, the neuraminidase inhibitors oseltamivir, zanamivir and peramivir have now become the prime antiviral drugs for the treatment of influenza A and B virus infections. For HCV infections, standard treatment consists of the combination of pegylated interferon-α with ribavirin, but several other antivirals targeted at specific viral functions such as the HCV protease and/or polymerase may be expected to soon take an important share of this important market. Still untapped is the potential of a variety of uncoating inhibitors, as well as protease and/or polymerase inhibitors against the wide spectrum of picornaviruses. While ribavirin has been available for 35 years as a broad-spectrum anti-RNA virus agent, relatively new and unexplored is favipiravir (T-705) accredited with activity against influenza as well as flaviviruses, bunyaviruses and arenaviruses.
Anti-Human Cytomegalovirus Activity of Constituents from Sasa Albo-Marginata (Kumazasa in Japan)
Authors: Sakai Asumi , Watanabe Kunitomo , Koketsu Mamoru , Akuzawa Kazuhiko , Yamada Rie , Li Zhuan , Sadanari Hidetaka , Matsubara Keiko , Murayama Tsugiya
Published: March 2015

Background:

Effective new anti-human cytomegalovirus (HCMV) agents and regimens need to be developed. We examined the anti-HCMV properties of crude extract (True World Extract of Bambuseae sasa [TWEBS]) and five compounds ( p-coumaric acid, 3-hydroxy-4-methoxyben-zaldehyde [vanillin], p-hydroxybenzaldehyde, 3-hydroxypyridine and 4',5,7-trihydroxy-3',5'-dimethoxyflavone [tricin]), isolated from Sasa albo-marginata, a bamboo known in Japan as Sasa.

Methods:

Among TWEBS and five compounds screened in a plaque reduction assay, four showed anti-HCMV activity in the MRC-5 human embryonic fibroblast cell line. The anti-HCMV mechanisms of the TWEBS was examined by western blot analysis using primary antibody specific for an immediate early (IE) antigen of HCMV, for a structural late antigen of HCMV and for β-actin.

Results:

Treatment of cells with ⩾0.001% of TWEBS inhibited the observable cytopathic effects of HCMV on infected cells. Western blot analysis demonstrated that TWEBS decreased the expression of IE antigen and late antigen of HCMV in the infected cells. Next, we examined the anti-HCMV properties of five compounds isolated from TWEBS. In a viral plaque reduction assay, tricin showed dose-dependent inhibitory properties with a 50% effective concentration of 0.17 µug/ml (selective index =1,205.8).

Conclusions:

The hot water extract (TWEBS) of Sasa albo-marginata, with tricin isolated from it, has anti-HCMV activity in MRC-5 cells. TWEBS and/or tricin are a novel compound with potential anti-HCMV activity. Future studies should evaluate these findings in vivo.
RNA-interference-based Gene Therapy Approaches to HIV Type-1 Treatment: Tackling the Hurdles from Bench to Bedside
Authors: Von Eije Karin J , Berkhout Ben
Published: March 2015

RNA interference (RNAi) is a cellular mechanism that can be induced by small interfering RNAs (siRNAs) to mediate sequence-specific gene silencing by cleavage of the targeted messenger RNA. RNAi can be used as an antiviral approach to silence HIV type-1 (HIV-1) through stable expression of precursors, such as short hairpin RNAs (shRNAs), which are processed into siRNAs that can elicit degradation of HIV-1 RNAs. At the beginning of 2008, the first clinical trial using a lentivirus with an RNA-based gene therapy against HIV-1 was initiated. The antiviral molecules in this gene therapy consist of three RNA effectors, one of which triggers the RNAi pathway. This review article focuses on the basic principles of an RNAi-based gene therapy against HIV-1, including delivery methods, target selection, viral escape possibilities, systems for multiplexing siRNAs to achieve a durable therapy and the in vitro and in vivo test systems to evaluate the efficacy and safety of such a therapy.
Sulfated Xylomannans from the Red Seaweed Sebdenia Polydactyla: Structural Features, Chemical Modification and Antiviral Activity
Authors: Ghosh Tuhin , Pujol Carlos Alberto , Damonte Elsa Beatriz , Sinha Sharmistha , Ray Bimalendu
Published: March 2015

Background:

Many viruses display affinity for cell surface heparan sulfate proteoglycans with biological relevance in virus entry. This raises the possibility of the application of sulfated polysaccharides in antiviral therapy.

Methods:

In this study, we analysed polysaccharide fractions isolated from Sebdenia polydactyla.

Results:

The purified xylomannan sulfate and its further sulfated derivatives showed strong activity against herpes simplex virus type-1 (HSV-1). Their 50% inhibitory concentration values were in the range 0.35–2.8 µg/ml and they lacked cytotoxicity at concentrations up to 1,000 µg/ml. The major polysaccharide, which had 0.6 sulfate groups per monomer unit and an apparent molecular mass of 150 kDa, contained a backbone of α-(1→3)-linked D-mannopyranosyl residues substituted at position 6 with a single stub of ß-D-xylopyranosyl residues.

Conclusions:

The degree of sulfation seemed to play an important role because desulfation and/or further sulfation of the isolated macromolecules largely influenced their in vitro anti-HSV-1 activity.
HIV Type-1 Entry Inhibitors with a New Mode of Action
Authors: Fink Ryan C , Roschek Bill , Alberte Randall S
Published: March 2015

Background:

The development of antiviral drugs has provided crucial new means to mitigate or relieve the debilitating effects of many viral pathogens. Regular use of these drugs has led to generation of resistant strains, making the control of many viral infections very difficult, particularly in HIV-seropositive and AIDS patients. A rich source for the discovery of new HIV infection inhibitors has been, and continues to be, the ‘mining’ of the large diversity of compounds already available in nature, and specifically those from botanical extracts.

Methods:

Using a newly developed direct binding assay with mass spectrometry technology (direct analysis in real-time time-of-flight mass spectrometry), we were able to show that compounds present in extracts of elderberry, cinnamon and green tea bind to and block HIV type-1 (HIV-1) infection in target cells.

Results:

The compounds that blocked HIV-1 infection were flavonoids and A-type proanthocyanidins. The 50% inhibitory concentration values of these extracts ranged from 0.5 to 201 µg/ml for four different HIV-1 serotypes. Interaction matrices with the elderberry extract and enfuvirtide, a peptide HIV-1 fusion inhibitor, revealed significant super additive effects. This indicates that the compounds in elderberry that prevent HIV-1 infection are likely to bind to viral glycoproteins other than gp41 (the binding site for enfuvirtide).

Conclusions:

Optimized elderberry, green tea and cinnamon extracts rich in certain flavonoid compounds were shown to block HIV-1 entry and infection in GHOST cells. As such, these types of botanical extracts could provide a starting point for the development of possible safe and reliable cotherapies for HIV-1-positive individuals, as well as for the identification of new small molecules as leading drug candidates for HIV-1 therapeutics and microbicides.
Identification of HIV-1 Integrase Inhibitors Based on a Four-Point Pharmacophore
Authors: Hong H , Neamati N , Winslow HE , Christensen JL , Orr A , Pommier Y , Milne GWA
Published: March 2015

The rapid emergence of human immunodeficiency virus (HIV) strains resistant to available drugs implies that effective treatment modalities will require the use of a combination of drugs targeting different sites of the HIV life cycle. Because the virus cannot replicate without integration into a host chromosome, HIV-1 integrase (IN) is an attractive therapeutic target. Thus, an effective IN inhibitor should provide additional benefit in combination chemotherapy. A four-point pharmacophore has been identified based on the structures of quinalizarin and purpurin, which were found to be potent IN inhibitors using both a preintegration complex assay and a purified enzyme assay in vitro. Searching with this four-point pharmacophore in the ‘open” part of the National Cancer Institute three-dimensional structure database produced 234 compounds containing the pharmacophore. Sixty of these compounds were tested for their inhibitory activity against IN using the purified enzyme; 19 were found to be active against IN with IC50 values of less than 100 µM, among which 10 had IC50 values of less than 10 µM. These inhibitors can further serve as leads, and studies are in progress to design novel inhibitors based on the results presented in this study.
Synthesis, Anti-Human Immunodeficiency Virus Activity and Esterase Lability of Some Novel Carboxylic Ester-Modified Phosphoramidate Derivatives of Stavudine (d4T)
Authors: McGuigan C , Sutton PW , Cahard D , Turner K , O'Leary G , Wang Y , Gumbleton M , De Clercq E , Balzarini J
Published: March 2015

We report the design, synthesis and antiviral evaluation of a series of lipophilic, masked phosphoramidate derivatives of the anti-human immunodeficiency virus (HIV) nucleoside analogue d4T, designed to act as membrane-soluble prodrug forms for the free nucleotide. In particular, we report a series of 12 novel compounds with systematic variation in the structure of the carboxylate ester function. In order to rationalize the changes in antiviral action with variation of this moiety we applied our recently developed 31P NMR-based assay for carboxyesterase lability to this series. However, no clear positive correlation emerged, indicating that, at least within this series, factors other than simple esterase lability may be the major determinants of antiviral potency.
Anti-Picornavirus Activity of Synthetic Flavon-3-yl Esters
Authors: Conti C , Mastromarino P , Sgro R , Desideri N
Published: March 2015

The in vitro antiviral activity against picornaviruses (rhinovirus serotype 1B and 14, and poliovirus type 2) of new synthetic 3-hydroxyflavones, 3-acetoxyflavones, and substituted cinnamic and benzoic acid flavon-3-yl esters was evaluated. The maximum non-toxic concentration of compounds was determined in a human cell line (HeLa) suitable for the replication of the three viruses. Their antiviral potency was measured by a plaque reduction assay. Generally, rhinoviruses exhibited a higher sensitivity to the new flavonoids than poliovirus. Flavones, with sterically small substituents in position 3, showed good activity against both rhinoviruses tested. However, the introduction of bulky substituents in the same position resulted in analogues with a higher toxicity and often with a lower efficacy.
Pyrido [1,2a] Indole Derivatives Identified as Novel Nonnucleoside Reverse Transcriptase Inhibitors of Human Immunodeficiency Virus Type 1
Authors: Taylor DL , Ahmed PS , Chambers P , Tyms AS , Bedard J , Duchaine J , Falardeau G , Lavallée JF , Brown W , Rando RF , Bowlin T
Published: March 2015

Pyrido [1,2a] indole derivatives were identified as potent inhibitors of human immunodeficiency virus type 1 (HIV-1) replication during a random screening programme. The compounds showed no antiviral activity against HIV-2 or in cells chronically infected with HIV-1, but had good inhibitory effect against purified HIV-1 reverse transcriptase (RT) in an in vitro assay. They were therefore classified as nonnucleoside RT inhibitors (NNRTI). The synthesis of additional compounds of the same class revealed a structure—activity relationship. The most potent compound of the series, BCH-1, had similar antiviral activity to the licensed NNRTI nevirapine against laboratory strains of HIV-1 cultured in cell lines and primary clinical isolates of HIV-1 cultured in peripheral blood mononuclear cells. However, BCH-1 showed greater cytotoxicity, providing a narrow selectivity index in the order of 35. BCH-1 had equivalent antiviral activity against viruses resistant to the nucleoside RT inhibitors zidovudine, didanosine and lamivudine and maintained better activity (less than threefold change in IC50) than nevirapine against viruses resistant to a range of NNRTIs with the single amino acid changes L100I, K103N, E138K or Y181C in the RT. Viruses with single V106A or Y188C amino acid changes showed five- and 10-fold resistance to BCH-1, respectively, in contrast to nevirapine, which had a >100-fold change in IC50. However, virus with both V106A and Y188C amino acid changes showed higher level resistance (>15-fold) to BCH-1. Virus with >10-fold resistance to BCH-1 was rapidly selected for after growth in increasing concentrations of compound and was shown to be cross-resistant to nevirapine. Sequencing of this virus revealed two amino acid changes at positions 179 (V to D) and 181 (Y to C) in the RT. BCH-1 represents a new class of NNRTI, which may act as a lead to identify more selective compounds.
Cell-Based and Animal Models for Hepatitis B and C Viruses
Authors: Schinazi Raymond F , Ilan Ehud , Black Paul L , Yao Xuejen , Dagan Shlomo
Published: March 2015

Reliable cell-based assays and animal models have been developed for evaluating agents against hepatitis B virus. Although much progress has been made, in vitro and in vivo assays for hepatitis C virus are still on the horizon. Advances towards establishing inexpensive and reliable experimental models have accelerated the development of therapeutic modalities for these life-threatening viral infections. The characterization of well-defined viral targets coupled with improved molecular diagnostic technologies have illuminated this field.
The Design and Synthesis of Potent Inhibitors of Hepatitis C Virus NS3–4A Proteinase
Authors: Attwood MR , Bennett JM , Campbell AD , Canning GGM , Carr MG , Conway E , Dunsdon RM , Greening JR , Jones PS , Kay PB , Handa BK , Hurst DN , Jennings NS , Jordan S , Keech E , O'Brien MA , Overton HA , King-Underwood J , Raynham TM , Stenson KP , Wilkinson CS , Wilkinson TCI , Wilson FX
Published: March 2015

Hepatitis C virus (HCV) is the cause of the majority of transfusion-associated hepatitis and a significant proportion of community-acquired hepatitis worldwide. Infection by HCV frequently leads to persistent infections that result in a range of clinical conditions including an asymptomatic carrier state, severe chronic active hepatitis, cirrhosis and, in some cases, hepatocel-lular carcinoma. The HCV genome consists of a single-stranded, positive sense RNA containing an open reading frame of approximately 9060 nucleotides. This is translated into a single polyprotein of approximately 3020 amino acids (C-E1-E2-p7-NS2-NS3-NS4A-NS4B-NS5A-NS5B), which in turn is processed by a series of host and viral proteinases into at least 10 cleavage products. The N-terminal portion of the NS3 protein encodes a serine proteinase that is responsible for the cleavage at the NS3–4A, NS4A-4B, NS4B-5A and NS5A-5B junctions. The 54 amino acid NS4A protein is a cofactor that binds to the NS3 protein and enhances its proteolytic activity. This report describes the expression of a recombinant NS3–4A proteinase fusion protein in Escherichia coli and the in vitro characterization of the enzyme activity using synthetic peptide substrates. It then demonstrates how these results were employed to guide the design of potent inhibitors of this enzyme.
Characterization of Human Immunodeficiency Virus Type 1 Strains Resistant to the Non-Nucleoside Reverse Transcriptase Inhibitor RD4–2217
Authors: Fujiwara Masatoshi , Kodama Eiichi N , Okamoto Masayuki , Tokuhisa Kenji , Ide Teruhiko , Hanasaki Yasuaki , Katsuura Kimio , Takayama Hiromitsu , Aimi Norio , Mitsuya Hiroaki , Shigeta Shiro , Konno Kenji , Yokota Tomoyuki , Baba Masanori
Published: March 2015

The non-nucleoside reverse transcriptase (RT) inhibitor RD4–2217 is a thiadiazole derivative that has proved to be a highly potent and selective inhibitor of human immunodeficiency virus type 1 (HIV-1) replication in vitro. In this study we examined genotypic and phenotypic characteristics of RD4–2217-resistant mutants that have been obtained by serial passage of HIV-1 in MT-4 cells in the presence of increasing concentrations (0.05, 0.25, 1 and 10 μM) of the compound. The strains obtained, IIIB/2217RE/0.05 and IIIB/2217RE/0.25, were two-and 15-fold resistant to RD4–2217, respectively, whereas IIIB/2217RE/1 and IIIB/2217RE/10 displayed 161-and >238-fold resistance, respectively. Both IIIB/2217RE/1 and IIIB/2217RE/10 had two amino acid substitutions, V189I and T240I, in the RT. Furthermore, RD4–2217 did not inhibit the replication of an HIV-1 molecular clone, which had the same mutation, at concentrations up to 10 μM, indicating that the V189I plus T240I mutation confers high-level resistance to RD4–2217. Interestingly, the replicability of IIIB/2217RE/1 and IIIB/2217RE/10 appeared to be lower than that of wild-type IIIB in MT-4 cells, suggesting that the V189I plus T240I mutation may impair the enzymatic activity of HIV-1 RT.
2′-Deoxy-5-Ethyl-β-4′-Thiouridine Inhibits Replication of Murine Gammaherpesvirus and Delays the Onset of Virus Latency
Authors: Barnes A , Dyson H , Sunil-Chandra NP , Collins P , Nash AA
Published: March 2015

The antiviral thionucleoside analogue 2′-deoxy-5-ethyl-β-4′-thiouridine (4′-S-EtdU) was shown to be a more potent inhibitor of gammaherpesvirus infection than acyclovir. This compound inhibits replication of murine herpesvirus (MHV)-68 in the lungs of mice when given 3 days post-infection. However, as with other nucleoside analogues, it was unable to prevent the establishment of latency, despite delaying the onset of latent infection in the spleen. In contrast, virus persistence in the lung was inhibited following drug treatment, although persistence was re-established in mice when treatment was suspended after 12 days. These data suggest that 4′-S-EtdU is a highly effective inhibitor of murine gammaherpesvirus replication and as such provides a powerful tool to study the pathogenesis of this virus in vivo.
Neoglycolipid Conjugates of Foscarnet with Enhanced Antiviral Activity in Cells Infected with Human Cytomegalovirus and Herpes Simplex Virus Type 1
Authors: Maloisel Jean-Luc , Pring Brian G , Tidén Anna-Karin , Dypbukt Jeannette , Ljungdahl-Ståhle Ewa
Published: March 2015

The synthesis of a series of neoglycolipid conjugates of foscarnet as potential drug targeting forms or lipophilic prodrugs of foscarnet is described. The compounds were obtained from suitably protected neoglycolipids, in which the lipid chain consisted of 12 to 20 carbon atoms, by ethoxycarbonylphosphonylation at the 6-hydroxyl or 4-hydroxyl group followed by deprotection. The in vitro antiviral activity of the compounds was determined in human foetal lung cells infected with human cytomegalovirus (HCMV) or herpes simplex virus type 1 (HSV-1). Compounds in which the lipid chain consisted of 14 to 20 carbon atoms showed pronounced antiviral activity against HCMV and HSV-1, the highest activity being shown by trans-9-octadecen-1-yl 6- O-carboxyphosphonyl-α-D-glucopyranoside against HCMV (approximately 50 times that of foscarnet) and by eicosyl 6- O-carboxyphosphonyl-β-D-galactopyranoside against HSV-1 (approximately 15 times that of foscarnet). Cytotoxicity was determined by assessing the capability of mitochondrial enzymes to metabolise MTT and gave TC50 values for the compounds that were 30 to 350 times higher than their IC50 values against HCMV and 5 to 15 times higher than their IC50 values against HSV-1. Foscarnet was not liberated on incubation of n-tetradecyl 6- O-carboxyphosphonyl-á-D-glucopyranoside with rat liver or intestine homogenate, neither could the neoglycolipid conjugate nor foscarnet be detected in rat plasma following oral administration. Further metabolic and pharmacokinetic studies are required in order to determine whether neoglycolipid conjugates of foscarnet can find a use as drug targeting forms of foscarnet.
How Motivated Reasoning and Temporal Frames May Polarize Opinions About Wildlife Disease Risk
Authors: Roh Sungjong , McComas Katherine A. , Rickard Laura N. , Decker Daniel J.
Published: March 2015

We draw from theories of motivated reasoning, dual-processing models, and attribution of responsibility to examine how scientific messages may increase public polarization with respect to emerging risk issues such as Lyme disease. A nationally representative sample of Americans ( N = 460) read messages about Lyme disease that varied the framing of responsibility for the prevalence of the disease (human/wildlife vs. wildlife only) and when its effects will occur (today vs. in the next 10 years). The influence of framing was contingent on participants’ partisanship, which resulted in a boomerang effect among Republicans and increased the degree of political polarization regarding support for proenvironmental behaviors.
The biopolitics of global health: Life and death in neoliberal time
Authors: Kenny Katherine E.
Published: March 2015

The opening years of the 21st century have witnessed the rise of ‘global health’ as the preferred label for attempts to govern the health of the global population. In this article, I locate the epistemological origins of global health in the introduction of the Disability Adjusted Life Year (DALY) metric in the World Bank’s Investing in Health report. I argue that the DALY metric accomplishes an economization of life by disaggregating lifetimes into component units of time and reassembling life as a revenue stream to be maximized through practices of self-investment in one’s own health – configured here as human capital. Life is reimagined as time and the individual as a neoliberal homo oeconomicus: as an entrepreneur of the self. I argue that the DALY metric is best conceived as a biopolitical technology of power that underpins the contemporary neoliberal global health regime.
Assembling ‘the bioeconomy’: Exploiting the power of the promissory life sciences
Authors: Petersen Alan , Krisjansen Ivan
Published: March 2015

Over the last decade, many governments around the world have embraced the concept of the bioeconomy and its promise to provide a ‘new engine of growth’ and deliver significant health and environmental benefits in the future. Drawing on ideas from the sociology of science and economic sociology, and focusing on the biomedical technology sector, this article examines the sociopolitical significance of the promissory discourse of the bioeconomy. We argue that this discourse plays a crucial performative role in contemporary biopolitics, in mobilising actor networks, attracting venture capital and research funding, and shaping the possibilities for action. However, for reasons that we outline and as the Australian experience in the biotechnology sector illustrates, the performativity of ‘the bioeconomy’ is prone to failure. The article concludes by considering the implications of promissory discourse for anticipatory governance in relation to science and for scientific practice.
Of ladders and looms: Moving through Walter Benjamin’s ‘Storyteller’
Authors: Erami Narges
Published: March 2015

In this article I take a closer look at Walter Benjamin’s essay ‘The Storyteller’ by connecting the craft of carpet weaving to storytelling. I reveal that Benjamin has encoded a ladder in his essay through his seemingly fragmentary ruminations or ‘philosophical observations’. I attempt a genealogy of ‘The Storyteller’, where I recognize that the ladder is an inspiration from Jewish mystical tradition, the Kabbala, where the cycle of life is realized and interpreted. I trace this ladder of experience through my own fieldwork on Persian carpets where I argue the importance of carpet weaving for the art of storytelling and vice versa, and in turn its implications and possibilities for recounting ethnographic accounts. By examining Benjamin’s writing on the craft of the artisan and his concept of experience, I explore the significance of storytelling as an ethnographic and experiential art.
A Clinically Oriented Perspective on Psychogenic Nonepileptic Seizure–Related Emergencies
Authors: Dworetzky Barbara A. , Weisholtz Daniel S. , Perez David L. , Baslet Gaston
Published: March 2015

Psychogenic nonepileptic seizures (PNES) can present emergently and are often mistaken for epileptic seizures. PNES emergencies have not been well studied, and yet there are associated serious morbidities, particularly when patients are seen in an emergency setting and are misdiagnosed. PNES may be prolonged, mimicking status epilepticus, a condition we refer to as nonepileptic psychogenic status (NEPS), and patients may receive aggressive and unnecessary medical treatments that can lead to serious iatrogenic complications, including death. NEPS is also associated with an increased risk of self-harm, including suicide attempts, and may indicate a serious comorbid psychiatric illness. In addition to iatrogenic complications of PNES, accidents and injuries are an underrecognized source of morbidity. PNES may also present during medical procedures, which may not only interfere with their completion, but may alarm practitioners who, fearing liability, may initiate further medical evaluations and treatments. When PNES occur during pregnancy, patients may be misdiagnosed with eclampsia and their offspring delivered prematurely. They also risk being placed on medications that are harmful to the fetus. Increased awareness of PNES is necessary to prevent iatrogenic harm and to identify underlying psychiatric illnesses that carry their own risks. As yet, data available to guide treatment are scant, and further study is needed.
Cognitive Impairment and Evaluation in Psychogenic Nonepileptic Seizures
Authors: Willment Kim , Hill Melanie , Baslet Gaston , Loring David W.
Published: March 2015

Neuropsychological studies comparing patients with psychogenic nonepileptic seizures (PNES) to those with epilepsy have been largely equivocal. The variability in the neuropsychological literature highlights the heterogeneity of the PNES population across a number of psychiatric and neurologic factors. Phenotypic presentations in PNES arise from complex interactions between vulnerable cognitive and emotional systems. We propose that variability in neuropsychological findings in PNES emerge in the context of diverse psychiatric, neurologic, and clinical factors. Traditional assessments that fail to integrate cognitive and emotional/behavioral profiles sufficiently would fall short in characterizing the complexity of brain-behavior relationships in this population. To advance the neuropsychology of PNES, we propose a systematic approach to measure a number of factors that influence cognitive impairment in this population. We begin by reviewing the current neuropsychological literature in PNES and discussing a number of factors that influence cognitive deficits. We then present a comprehensive neuropsychological battery designed to capture elements (cognitive dysfunction, psychopathology, emotion processing deficits) underlying the proposed vulnerable cognitive-emotional system in PNES. It is our hope that the proposed battery will facilitate the aggregation of data across neuropsychological investigations, to allow more advanced statistical analyses, and ultimately enhance our understanding of PNES and the development of effective management and treatment options.
Efficacy of N-methanocarbathymidine against genital herpes simplex virus type 2 shedding and infection in guinea pigs
Authors: Bernstein David I , Bravo Fernando J , Pullum Derek A , Shen Hui , Wang Mei , Rahman Aquilur , Glazer Robert I , Cardin Rhonda D
Published: March 2015

Background

Current approved nucleoside therapies for genital herpes simplex virus (HSV) infections are effective but improved therapies are needed for treatment of both acute and recurrent diseases.

Methods

The effects of N-methanocarbathymidine were evaluated and compared to acyclovir using guinea pig models of acute and recurrent infection. For acute disease following intravaginal inoculation of 106 pfu HSV-2 (MS strain), animals were treated intraperitoneally beginning 24 h post-infection, and the effects on disease severity, vaginal virus replication, subsequent recurrences, and latent virus loads were evaluated. For evaluation of recurrent infection, animals were treated for 21 days beginning 14 days after infection and disease recurrence and recurrent shedding were evaluated.

Results

Treatment of the acute disease with N-methanocarbathymidine significantly reduced the severity of acute disease and decreased acute vaginal virus shedding more effectively than acyclovir. Significantly, none of the animals developed visible disease in the high-dose N-methanocarbathymidine group and this was the only group in which the number of days with recurrent virus shedding was reduced. Treatment of recurrent disease was equivalent to acyclovir when acyclovir was continuously supplied in the drinking water.

Conclusion

N-methanocarbathymidine was effective as therapy for acute and recurrent genital HSV-2 disease in the guinea pig models.
Aussie kids, global citizens: Cultural nationalism and cosmopolitanism in service providers’ and parents’ accounts
Authors: Nichols Sue
Published: March 2015

Based on interviews with Australian parents and service providers and examination of parenting resources, this study examined the respective influence of cultural nationalism and cosmopolitanism on parenting in the early years. This analysis found, contrary to research on children’s social identities, that ideas of nation were significant to Australian parents and service providers. However, there are significant challenges to articulating and resourcing a vernacular orientation to family life. These include the dominance by multinational enterprises of the marketplace for parenting resources, the generic nature of these resources and the difficulty in defining what an Australian family or parenting style might be. At the same time, some parents identified with a cosmopolitan orientation to socialising their children. Their motivations were various, including future transnational mobility, conferring advantage in a competitive local job market and fostering an appreciation for diverse cultures. This was a strategic and entrepreneurial rather than a philosophical orientation.
A 100 smart cities, a 100 utopias
Authors: Datta Ayona
Published: March 2015

In my response to the commentaries on my anchor article, I have taken on board the key question of how and why India has become the site of production of 100 proposed smart cities. I forward a notion of ‘technocratic nationalism’ to suggest that it is the young urban population in India who have largely bought into the smart city dream. Whilst drawing encouragement from the largely positive commentaries on my article, I then take on three main critiques of the article – first, that it has inadvertently promoted a hegemony of ‘city-ness’ by focusing on the imagined smart city to be; second, that the smart city has strong connections with colonial urban planning and third, whether Dholera should be considered the first smart city at all. I suggest that the article’s city-ness and postcolonial links to India’s urban planning is both political and heuristic, since it is the postcolonial ‘urban’ moment where India has situated its moment of modernity globalization and economic power. I contend that the final critique is based on a misinterpretation of the use of the word ‘first’, which was always intended to reflect a politics of innovation among cities. Finally, I suggest that the other ‘gaps’ in my article highlighted by one of the commentators is not a gap, rather beyond the scope and objectives of an exploratory article such as this.
Utopian urbanism and representational city-ness
Authors: Jazeel Tariq
Published: March 2015

This commentary responds to Ayona Datta’s critique of India’s smart city agenda by emphasizing the representational work that urban futures require. In the context of Dholera smart city, I draw attention to the discursive terrains – around city-ness and utopianism in particular – mobilized by the state in order to normalize the inevitability of exclusionary urban planning and imaginations. I suggest these representational fields are key battlegrounds for critical urban geography.