bluuebunny/crossref_metadata_2025 huggingface dataset:
Visions of Violence: Christianity and Anti-Humanism in Patricia Highsmith's Ripliad
Authors: Dill Scott
Published: May 2015

Though it may seem godlessly immoral, the celebration of violence in Patricia Highsmith's Ripliad is rooted in a Calvinistic sense of sin and the vision of human freedom Highsmith discovered in Christian writers. Throughout the five novels composing her Ripliad, Tom Ripley ironically embodies the talents of Christ's primary antagonist—the Father of Lies—as Highsmith's embittered censure against the disappearance of evil as a meaningful psychological category in postwar culture.
The Bible as Comparative Literature
Authors: Hart Dabney
Published: May 2015

The membership of the Conference on Christianity and Literature is comprised largely of teachers, many of whom bring their scholarly concerns to bear in courses such as The Bible and Literature or Religion and Literature. This section on Pedagogy offers a range of practical experience in that effort. Professor Dabney Hart of Georgia State University discusses an approach through comparative literature, while Professor Gweneth Schwab of the University of Illinois discusses an approach based upon balanced responses to literature. Professor Allena Longfellow has shared the introduction to an extensive annotated bibliography for her course in The Bible and Literature at the Louisiana State University. Professor Roy Battenhouse of Indiana University provides a focused outline for a literary analysis of the tragedy of Absalom. Finally, Professor Janet Catlin of Oscar Rose Junior College reminisces on her experience of teaching The Bible as Literature in Oklahoma.
Christianity and Literature: Covertly Public, Overtly Private
Authors: Marty Martin E.
Published: May 2015

This article is based upon an address to the Conference on Christianity and Literature at the Annual Convention of the Modern Language Association in Toronto on 29 December 1997. The invitation asked me to comment on the public/private distinction that I make as Director of the Public Religion Project and to accent the “cultural context,” which fits my History of Culture faculty assignment and three decades of writing Context, a newsletter relating religion to culture. I was to inform it theologically, which a divinity professor is supposed to be able to do, and to show some curiosity about the literary theme, as my decades-long stint as literary editor at The Christian Century should poise me to do. Under it all my limiting job description matches a badge provided me at a conference in Tübingen, where the hosts handed out identifications marked “Theologian of History,” “Theological Historian,” and “Historical Theologian.” Mine read simply, “Historical Historian.”—MEM
A Simple and Quick Technique for the Determination of Transfer Functions of Linear Mechanical Systems
Authors: Mashadi B.
Published: May 2015

Usual methods for the determination of the transfer functions of mechanical systems consisting of linear elements (i.e. mass, spring and damper), are practical only for simple cases. In a complicated system with many elements, the process is tedious and error-prone. In this work, with the aid of a simple model which easily transfers the system from time domain into the Laplace domain, the general forms of the transfer functions of the system have been derived. In this report, three general forms of such systems are discussed and examples are considered. The advantages of this method in addition to its simplicity are that the transfer functions provide numerators and denominators (characteristic equations) separately; the formulae are easily applicable in digital computer programs; and finally, the method can be used for academic purposes (for example, for quick problem-checking by the instructor).
Multicycle Approach to Power Cycle Studies
Authors: Cole G. H. A.
Published: May 2015

The thermodynamic behaviour of the Rankine cycle for steam and the Joule cycle for gases, together with the various modifications, are derived from a single approach based on that of the combined cycle. The possible modifications of the cycles are identified for steam and for gas, together with the relationships between the two cases. The arguments allow the input data for the steam cycle to involve conditions at the turbine exit.
The Efficiency at Maximum Power Output of Endoreversible Engines under Combined Heat Transfer Modes
Authors: Moukalled F.
Published: May 2015

A mathematical model for investigating the performance of endoreversible heat engines under combined conduction, convection, and radiation heat transfer modes is presented. The model is suitable to be introduced to engineering students attending a course in thermodynamics who may apply it to predicting the performance of real engines and a variety of energy conversion systems in a simplified manner. Results generated by the model show that the relative contribution of conduction/convection and radiation heat transfer modes deeply affect the efficiency at maximum power output. Moreover, a number of well-known formulae presented in several references are shown to represent special cases of the new formulation.
Practical Background of Engineering Students in Developing Countries
Authors: Olorunmaiye J. A.
Published: May 2015

One of the problems confronting engineering education in developing countries is that of inadequate technological background of students caused by the lack of industrial environment. Efforts made to solve this problem in Nigeria include exposing students to practical engineering through industrial training and running a two-year internship programme for engineering graduates. In addition to these, it is proposed that lecturers in third world countries can study indigenous technologies and use them as illustrative examples that students can identify with, where possible.
An Educational Two-Dimensional Interactive Dynamic Grid Generator
Authors: Darwish M. , Diab H. , Moukalled F.
Published: May 2015

This paper describes IDGG, an Interactive Dynamic Grid Generator, for use as an educational tool by students studying computational fluid dynamics. The package is a Windows applications and runs on IBM PC, or compatible, computers. It is written in Pascal and built using object-oriented programming. The computer program allows the user to generate boundary-fitted curvilinear grids in any two-dimensional domain. The procedure adopted requires the user to perform the transformation step by step allowing him/her to easily grasp the concept of boundary-fitted coordinate systems. In addition, IDGG may be used by CFD researchers to display results graphically in the form of vector fields, contours, and two- and three-dimensional plots. The examples provided show the effectiveness of the package as a teaching aid.
Teaching Engineering Field Theory Using IT
Authors: Gretton H. W. , Callender J. T. , Challis N. V.
Published: May 2015

In this paper it is argued that modern developments in technology, such as the spreadsheet, open out possibilities for different approaches to topics in engineering mathematics, for example field theory. The aim here is not to reduce mathematics for engineers to the level of pressing buttons, but it is to encourage a deeper understanding. The visualization capabilities of computer technology, and its strength in performing repetitive tasks, can allow and indeed encourage a review both of what mathematical skills and understanding are required of engineers now and also of the best approach to nurturing that understanding. For example in an approach to two- dimensional heat conduction, the initial emphasis may be shifted away from heavy manipulation and towards modelling, problem solving and building a conceptual framework. This allows students to develop an intuitive feel for typical problems before becoming entangled in some of the more complex analytical and mathematically sophisticated issues. The current example is only one of many where modern developments in technology may lead to a review of educational as well as engineering practice.
Design and Hands-on Experiences for Undergraduates: Case Study on Design, Construction and Testing of Small Aircraft Models
Authors: Finaish F.
Published: May 2015

This article describes the development of a new design course in the Aerospace Engineering curriculum at the University of Missouri-Rolla offered during the second (sophomore) year. The course is designed to offer learning opportunities that apply the fundamentals of design along with hands-on experience. The students are required to analyse and solve open-ended design problems, test and experiment with different concepts, build models that illustrate what they have proposed in the analysis phase, and use engineering process skills such as teamwork and development of technical reports. An emphasis is placed on the connection between theory and design applications, comparisons of analytical work with test results, reporting, and working with peers. Details of the course content, organization, and guidelines to develop small aircraft models along with the testing hardware needed are given.
Sensitivity of Mechanical Systems with One Viscous Damper: Application to a Uniform n-Mass Oscillator
Authors: Gürgöze M.
Published: May 2015

The structural design sensitivity problem of a discrete mechanical system with a single viscous damper is considered. The sensitivity of the eigenvalues and the eigenvectors with respect to the damping parameter is evaluated. Exact analytical expressions for the eigenvalues and the eigenvectors of the modified system are obtained in addition to approximate expressions. A uniform n-mass oscillator viscously damped by a single damper is taken as an application example. Good agreement between the exact and approximate formulae is observed.
An Optimization Approach to Vibration Isolation of Rigid Bodies
Authors: Heyns P. S.
Published: May 2015

The conventional single-degree-of-freedom approach to isolator design dealt with in most undergraduate curricula, is not always adequate for the design of practical isolator systems. In this article, an optimization approach to the design problem is presented and the viability of the approach demonstrated. It is, however, also shown that multiple local minima may exist and that due care should be exercised in the application of the method.
The Development of a Dynamic Balancing Machine
Authors: Ercoli Liberto , La Malfa Salvador
Published: May 2015

A prototype of a dynamic balancing machine has been developed and put to use in the mechanical engineering laboratory of the Faculty. The goal of this project is twofold: first, to cooperate with the Mechanical Engineering Department in offering to industry balancing services for industrial rotors and, secondly, to promote the teaching of static and dynamic, analytical and experimental balancing techniques in both graduate and undergraduate courses. The machine consists of a non-conventional mechanical system presenting some constructive and methodological advantages with respect to the conventional machines. The results achieved when balancing industrial rotors with the prototype are similar to those obtained with the commercial machines available.
Holographic Stereograms and Their Potential in Engineering Education in a Disadvantaged Environment
Authors: Reed B. I. , Gryzagoridis J.
Published: May 2015

The presentation of subject matter to students from disadvantaged backgrounds relies on using techniques that help them visualize various concepts and processes. Here an alternative demonstration technique is described, the holographic stereogram, where one can show some object or process behaving in the manner that it would in a real life environment. The method used to generate these stereograms is briefly described and an example is given as to how they can be integrated into an existing academic programme.
A Laboratory Project-Based Teaching Approach to Integrated Design
Authors: Lin J. , Ball A. A.
Published: May 2015

This paper presents an approach for demonstrating the interdependent and integrated nature of the engineering design process. The approach emphasizes the varied and multi-disciplinary nature of design so that students are aware of the importance and application of other course material. As an example, an air duct system is considered from its initial design through to its construction. This also provides an opportunity for students to understand the basic theory of surface development in sheet metal design and to carry out finite element (FE) stress analysis and air flow simulation in the first year of their undergraduate studies. The laboratory project-based approach is intended to encourage student interest and enthusiasm in integrated design.
New Virus-Selective Inhibitor of Terminal Glycosylation Increasing Immunological Reactivity of a Viral Glycoprotein
Authors: Olofsson S. , Datema R.
Published: May 2015

In previous reports we have shown that certain nucleoside analogues may be phosphorylated by herpesvirus-specified thymidine kinases, thereby acquiring an ability to act as virus-selective inhibitors of terminal glycosylation. In the present paper we report that the antiviral nucleoside analogue 5-propyl-2′-deoxyuridine induced a pattern of glycosylation inhibition, which resulted in an increased availability of the HSV-1-specified glycoprotein gC-1 for neutralizing antibodies. This effect, which was absent in cells infected with a thymidine kinase-deficient HSV mutant, was correlated with a decrease in the proportion of highly branched N-linked oligosaccharides associated with gC-1.
E-5-(2-Chlorovinyl)-2′-Deoxycytidine: Synthesis and Antiherpetic Activity
Authors: Kumar A. , Lewis M. , Shimizu S.-I. , Walker R. T. , Snoeck R. , De Clercq E.
Published: May 2015

E-5-(2-chlorovinyl)-2′-deoxycytidine (CVDC) has been prepared for the first time using an improved synthesis of the starting material E-5-(2-chlorovinyl)-2′-deoxyuridine (CVDU). CVDC and CVDU were only slightly less active against herpes simplex virus type 1 (HSV-1) and varicella-zoster virus (VZV) than the potent anti-herpes compound E-5-(2-bromovinyl)-2′-deoxyuridine (BVDU). The Z-forms of CVDC and CVDU were markedly less active against HSV-1 and VZV than the E-isomers. None of the compounds showed activity against thymidine kinase (TK)-deficient variants of HSV-1.
The Galactose-Specific Lectin from the Sponge Chondrilla Nucula Displays Anti-Human Immunodeficiency Virus Activity in vitro via Stimulation of the (2′-5′)Oligoadenylate Metabolism
Authors: Schröder H. C. , Kljajić Z. , Weiler B. E. , Gasić M. , Uhlenbruck G. , Kurelec B. , Müller W. E. G.
Published: May 2015

A new lectin has been isolated from the sponge Chondrilla nucula. The purified CN lectin is a protein composed of four polypeptide chains with a molecular weight (MW) of 15600. The isoelectric point is 4.5 and the amino acid composition is rich in aspartic and glutamic acid. The lectin precipitates erythrocytes from humans (A, B, O) with a titre between 25 and 210. The CN lectin is d-galactose-specific and displays a moderate mitogenic effect on spleen lymphocytes from mice and on CD4-positive human H9 cells. An interesting feature of this lectin is its ability to stimulate the (2′-5′)oligoriboadenylate [(2′-5′)A] metabolic pathway in non-infected and human immunodeficiency virus (HIV-1)-infected H9 cells. Moreover, HIV-1-infected H9 cells show an increase in the time period of HIV-1 release in response to CN lectin treatment. These data suggest that CN lectin causes a retardation of HIV-1 release due to further increase of the elevated intracellular level of (2′-5′)A.
In vitro Studies of the Antiviral Range of Cicloxolone sodium and Identification of Cell Lines Tolerant to the Drug
Authors: Galt C. , Dargan D. J. , Subak-Sharpe J. H.
Published: May 2015

To identify suitable host cells permissive for virus growth but resistant to the triterpenoid compound cicloxolone sodium (CCX), 18 cell lines were studied for tolerance to treatment for 48 h with increasing drug concentrations. IC50 values and replication indices of the IC50, at 300 μm CCX and in the absence of drug, were determined. Eight cell lines proved resistant, six sensitive and four intermediate in sensitivity to CCX. Four of the resistant cell lines were then selected as appropriate hosts for investigating the antiviral effect of CCX. Infectious yield dose–response experiments were carried out with viruses from eight different families comprising enveloped and non-enveloped DNA and RNA viruses. The RNA viruses included some with genomes that were segmented or non-segmented, positive-stranded, negative-stranded or double-stranded. No consistent relationship between sensitivity to CCX and any of these characteristics was found. Three classes of response were obtained: class 1 [VSV (Indiana), Influenza A, EHV-1 and BHV-1] showed a consistent, progressive CCX dose-dependent 100→100000-fold reduction in infectious virus yield; class 2 (Bunyamwera and Germiston, Polio-1, Reovirus-3 and Adenovirus-5) exhibited initial sensitivity (10–100-fold) but increasing the dose had minimal further effect on yield, with plateau values reached between 100 and 200 μm CCX; class 3 (SFV) appeared to be unaffected by CCX treatment. Plaque reduction assays revealed that HCMV and VZV are also highly sensitive to CCX inhibition.
Exploitation of a Rapid and Sensitive Assay to Analyse Transactivation of the Human Immunodeficiency Virus type 1 (HIV-1) Long Terminal Repeat
Authors: Roberts C. M. , Blair E. D.
Published: May 2015

Transregulation of the promoter within the 5′ long terminal repeat (LTR) of the human immunodeficiency virus (HIV) provirus determines the level of replication of HIV in latently, persistently or acutely infected cells. To measure rapidly the degree of transactivation of the HIV-1 LTR by various cellular and viral effectors, stably transformed cell lines containing integrated copies of the HIV LTR promoter (−122 to +80, relative to the major mRNA cap site) linked to the Escherichia coli lac Z gene were prepared by co-selection for pSV2 neo-mediated G418 resistance. One cell clone, RS 3/7, containing about 40 integrated copies of the recombinant LTR- lacZ gene was analysed further. RS 3/7 cells expressed high levels of β-galactosidase in response to co-transfection with plasmids expressing the HIV-1 transactivator, tat, infection with low multiplicities of herpes simplex virus type 1 (HSV-1), transfection with a plasmid expressing the HSV-1 immediate-early (IE) protein, ICPO, and by incubation with medium containing sodium butyrate. β-galactosidase activity was also induced by incubation of RS 3/7 cells with medium containing full length tat polypeptide. The cysteine analogue, D-penicillamine, previously reported as a potent inhibitor of tat-mediated transactivation (Chandra et al., 1988), was of limited efficacy in RS 3/7 cells transfected with tat-expressing plasmids. This cell line will be of value in identifying additional transactivators of the HIV-1 LTR, and in the selection of inhibitors of such effectors.
Isolation and Preliminary Characterization of Chalcone Ro 09-0410-Resistant Human Rhinovirus Type 2
Authors: Yasin S. R. , Al-Nakib W. , Tyrrell D. A. J.
Published: May 2015

We have isolated a human rhinovirus type-2 (HRV-2) mutant that is resistant to the antiviral agent chalcone Ro 09-0410 (4′-ethoxy-2′-hydroxy-4, 6′-dimethoxychalcone). This Ro 09-0410-resistant HRV-2 mutant (SR2-0410) exhibited altered biological properties when compared with the parental wild-type (wt) HRV-2. It was unstable when exposed to acid and heat in the presence of the drug, was incapable of producing plaques and produced an early cytopathic effect (CPE) at high temperatures (35°C and 37°C). Furthermore, compared with the parental wild-type, it showed a reduced ability to be neutralized by an anti-HRV-2 polyclonal serum and monoclonal antibodies. This SR2-0410 mutant demonstrated cross-resistance to other synthetic anti-rhinovirus compounds, which are also thought to bind to the viral capsid protein (VPI), such as 4′,6-dichloroflavan, 3-methoxy-6-[4-(3-methylphenyl)-I-piperazinyl] pyridazine (R 61837) and WIN 51711 (5-[7-[4-(4,5-dihydro-2-oxazolyl) phenoxyl] heptyl]-3-methyl-isoxazole). Furthermore, it was also resistant to various antiviral combinations synergistic against HRV-2. However, it was still sensitive to enviroxime [2-amino-I-(isopropyl sulphonyl)-6-benzimidazole phenyl ketone oxime], which has a different mode of action and is thought to interfere with viral RNA synthesis.
A Stereochemical Rationale for the Activity of Anti-HIV Nucleosides
Authors: Taylor E. W. , Van Roey P. , Schinazi R. F. , Chu C. K.
Published: May 2015

Crystallographic studies have shown that, in the solid state, nucleosides active against the human immunodeficiency virus (HIV) generally exhibit moderate to extreme S-type furanose conformations (pseudorotational phase angle up to 215°). Following this lead, it is shown that using principles of conformational analysis, one can rationalize the activity or inactivity of other nucleoside analogues (including many not yet studied by X-ray methods) in terms of the effects of substituents on the furanose ring conformation. An analysis of the various 1,4 interactions of the O4′ lone pairs, O4′ itself, and the substituents on C2′ and C3′ shows that S-type conformations are stabilized (relative to N-type) in all the active ribose analogues, whereas this effect is absent in most inactive compounds. The gauche effect is a major determinant of activity, and the O4′ lone pairs, which have been neglected in many previous force field studies, may also be involved in stabilizing extreme S-type conformations. In such conformations (particularly for P > 180°) the + sc orientation of O5′ is destabilized, increasing access to the ap orientation, which may be more favourable for activity.
Characterization of gp120 Binding to the CD4 Antigen and Detection of Specific Inhibitors
Authors: Kozlowski M. R. , Watson A.
Published: May 2015

The first step in the attack of human immunodeficiency virus (HIV-1) on human T lymphocytes is binding of the viral coat protein, gp120, to the CD4 antigen on the surface of the cells. The present study examines 125I-gp120 binding to CEM and U937 cells. The results of this study show that this process is more complex than previously thought, consisting of multiple binding components, some of which may reflect processes occurring after the actual binding. Despite its complexity, measurement of the inhibition of 125I-gp120 binding by monoclonal antibodies to the CD4 antigen or to gp120 generally parallels direct measurement of the inhibition of HIV-1 binding to cells expressing the CD4 antigen (CD4 positive). Furthermore, aurintricarboxylic acid and pentosan polysulphate, inhibitors of the association of HIV-1 with cells, also inhibit 125I-gp120 binding. This is the first case in which a small molecule has been shown to inhibit gp120 binding using a classical radioligand binding assay. Two other inhibitors of HIV-1 association with cells, dextran sulphate and chondroitin sulphate, were less effective as 125I-gp120 binding inhibitors, suggesting that prevention HIV-1/cell association can be produced by mechanisms other than direct inhibition of gp120/CD4 binding.
Synthesis of 2′- and 3′-Amino-Substituted Uridine, Thymidine and Adenosine, and Their Inhibitions of HIV Replication
Authors: Vial J.-M. , Johansson N. G. , Vrang L. , Chattopadhyaya J.
Published: May 2015

Reactions of primary and secondary amines with appropriately protected 2′- O-mesyl-3′-deoxynucleosides 1, 5, and 18 gave 2′,3′-dideoxy-2′-alkylaminonucleosides 2a-d, 6a-c and 19a-d, f, n-q (35–40%) as well as a small amount of 2′,3′-glyceropentofuranosyl nucleoside 3, 7 or 11 (∼15%). Displacement of the 3′- O-mesyl group in 9b with amines gave mainly the elimination product 11, except in the reaction with morpholine and benzylamine which gave 3′-amino-substituted products 10c and 10d at a yield of 52% and 24%, respectively. The ring-opening reactions of appropriately protected 2′, 3′,- O-lyxoanhydro-adenosine 13 by a variety of primary and secondary amines gave isomeric mixtures of 2′-alkylamino nucleosides 15a-k (∼20%) and 3′-alkylamino nucleosides 14a-m (∼60%). These alkylamino nucleosides have been subsequently deprotected under acidic conditions to give the parent nucleosides in good yields; their biological activities as inhibitors of human immunodeficiency virus (HIV) replication have been also evaluated. The 2′,3′-dideoxy-2′-substituted and 2′,3′-dideoxy-3′-substituted nucleosides described herein are not available through any other known routes.
Flavonoids: Potent Inhibitors of Poliovirus RNA Synthesis
Authors: González M. E. , Martínez-Abarca F. , Carrasco L.
Published: May 2015

Some naturally occurring flavonoids, such as 3-methyl quercetin and Ro-090179, show potent anti-picornavirus activity. They inhibit poliovirus replication at concentrations 100-fold or 1000-fold lower than hydroxybenzyl-benzimidazole (HBB) and guanidine, respectively. Ro-090179 selectively blocks viral RNA synthesis in poliovirus-infected HeLa cells more strongly than 3-methyl quercetin and is therefore the most potent and selective inhibitor of poliovirus RNA synthesis described until now. In addition, Ro-090179 discriminates in its inhibition between plus- and minus-stranded RNA synthesis. Thus, analysis of the viral RNA made in poliovirus-infected cells when the compound is added late in the infection cycle, indicates that the synthesis of genomic RNA is potently blocked, whereas minus-stranded RNA synthesis is not inhibited. These findings make Ro-090179 a valuable compound for obtaining insight into the molecular mechanisms of poliovirus RNA replication.
Inhibition of Phlebovirus Infections in vivo by Tiazofurin and Selenazofurin
Authors: Smee D. F. , Huffman J. H. , Hall L. L. , Huggins J. W. , Sidwell R. W.
Published: May 2015

The c-nucleosides tiazofurin and selenazofurin were evaluated in mice against the Adames strain of Punta Toro virus, a Phlebovirus related to Rift Valley fever and sandfly fever viruses. When administered subcutaneously (s.c.) twice a day for 5 days starting 4h before virus inoculation, tiazofurin reduced mortality, hepatic icterus scores, serum aspartate aminotransferase (AST) levels, and serum virus titres at 250–500 mg kg−1 day−1. Liver virus titres were not reduced in these treated animals, however. Oral tiazofurin treatment was effective by the same criteria at 375 and 750 mg kg−1, except that liver virus titres were reduced at 750 mg kg−1. Similar effects were observed with selenazofurin given s.c. (80–160 mg kg−1) or orally (80–320 mg kg−1) for 5 days. Selenazofurin suppressed liver virus titres by oral but not s.c. treatment. In a time-course study tiazofurin was effective s.c. at 250–1000 mg kg−1 when administered once only at 48 h after virus inoculation, whereas treatments at 4, 24, 72 and 96 h were less or not effective. By comparison with published results, tiazofurin and selenazofurin do not appear to be as active or selective as ribavirin and ribamidine against Punta Toro virus infections in mice.
Stability of the Herpesvirus Ribonucleotide Reductase-Inhibiting Nonapeptide YAGAVVNDL in Extracts of HSV-1-Infected Cells
Authors: Telford E. , Owsianka A. , Marsden H.
Published: May 2015

The nonapeptide YAGAVVNDL has previously been shown to specifically inhibit ribonucleotide reductase (RR) induced by herpes simplex virus (HSV) and other herpesviruses. The stability of this peptide has been examined in extracts of HSV-infected cells. It was found to be rapidly modified to yield free tyrosine and the octapeptide AGAWNDL. Modification could be inhibited by several protease inhibitors, suggesting that it arises through cleavage of the amino-terminal tyrosine peptide bond. The implications of these results for the development of a therapeutically useful drug based on the nonapeptide are discussed.
Anti-Herpetic Activity of (±)-(1α, 2β, 3α)-9-[2-Hydroxy-3-(Hydroxymethyl)Cyclobutyl]Guanine and Inhibition of HSV-1 DNA Polymerase
Authors: Terry B. J. , Mazina K. E. , Tuomari A. V. , Hagen M. E. , Haffey M. L. , Jacobs G. A. , Zahler R. , Field A. K.
Published: May 2015

A novel nucleoside analogue, (±)-(1α, 2β, 3α)-9-[2-hydroxy -3-(hydroxymethyl)cyclobutyl]guanine [(±)-HHCG] was synthesized and has antiviral activity against herpes simplex virus (HSV) types 1 and 2, human cytomegalovirus (HCMV) and varicella-zoster virus (VZV) in plaque reduction assays. The antiviral activity of (±)-HHCG against HSV-2 shows a 10-40-fold dependence on the presence of a virally encoded thymidine kinase. (±)-HHCG is a substrate for HSV-1 thymidine kinase with a phosphorylation rate of 28 μm h−1 compared to 15 μm h−1 for acyclovir under identical conditions. Enzymatically prepared HHCG-triphosphate is a competitive inhibitor of dGTP incorporation into DNA by HSV-1 DNA polymerase with an inhibition constant corresponding to 0.0077 μm. Hybridization studies using an HSV-1-specific DNA probe indicated that DNA synthesis is reduced in HSV-1-infected WI-38 cells treated with (±)-HHCG, with an ED50 comparable to that of acyclovir. These results suggest that the antiviral activity of (±)-HHCG is due to preferential inhibition of viral DNA synthesis.
Effect of Daily Zidovudine (AZT) Pulse-Therapy on Replication of Human Immunodeficiency Virus Type 1 and Type 2 in vitro
Authors: Vogt M. W. , Schwarz C. , Kuster H. , Nadai V. , Siegenthaler W. , Lüthy R.
Published: May 2015

Zidovudine (3′-azido-3′-deoxythymidine, azidothymidine) has demonstrated clinical efficacy in patients with acquired immunodeficiency syndrome (AIDS) and related disorders but toxicity often limits its use. Employing an in vitro cell-culture model we compared the antiviral effect and cytotoxicity of a single daily pulse exposure of 10 μm for 60 min with a continuous exposure of 1 μm. In patients these concentrations correspond approximately to a single oral daily dose of 1 g zidovudine and to a conventional oral zidovudine therapy with four to six daily doses, respectively. Replication of human immunodeficiency virus type 1 (HIV-1) and type 2 (HIV-2) was inhibited in cultured peripheral blood mononuclear cells equally well with both regimens. No differences in cytotoxicity were observed and intracellular concentrations of zidovudine triphosphate were comparable. It is conceivable that single daily doses of zidovudine might be equally efficacious as several daily doses. Using single daily doses would facilitate patient compliance and the concept should therefore be explored in clinical trials.
Synthesis and anti-HIV Activity of Some Novel Substituted Dialkyl Phosphate Derivatives of AZT and ddCyd
Authors: McGuigan C. , O'Connor T. J. , Nicholls S. R. , Nickson C. , Kinchington D.
Published: May 2015

The reaction of thymidine, AZT (Fig. 1, compound 1) and ddCyd (Fig. 1, compound 2) with bis(2,2,2-trichloroethyl) phosphorochloridate gave novel 5′-bis(2,2,2-trichloroethyl) phosphates, characterized by spectroscopic and analytical data. Analogous reactions with bis(2,2,2-trifluoroethyl) phosphorochloridate gave the corresponding AZT and ddCyd derivatives. In both of the ddCyd reactions, by-products were isolated and characterized as O5′, W4-diphosphorylated materials. It was hoped that the 5′-phosphate triesters might act as membrane-soluble pro-drugs of the bio-active free nucleotides of AZT or ddCyd. In fact, all of the 5′-phosphate derivatives of AZT and ddCyd displayed anti-HIV activity in vitro. Surprisingly, the thymidine compound also displayed very slight anti-HIV activity. The striking activity of the AZT and ddCyd derivatives is attributed to the metabolic instability of the substituted trialkyl phosphate moiety.
Inefficient Phosphorylation of 3′-fluoro-2′-dideoxythymidine in Liver Cells May Explain its Lack of Inhibition of Duck Hepatitis B virus Replication in vivo
Authors: Löfgren B. , Habteyesus A. , Nordenfelt E. , Eriksson S. , Öberg B.
Published: May 2015

Duck hepatitis B virus (DHBV) was used as a model in the search for antiviral compounds against hepatitis B. The triphosphate of 3′-fluoro-2′,3′-dideoxythymidine (FLT) inhibits DHBV DNA polymerase in vitro. The aim of this investigation was to evaluate the in vivo inhibitory effect of FLT on DHBV in ducks. Four DHBV-positive ducklings were treated with FLT by intraperitoneal injections of 25 mg kg−1, two times daily for 17 days. No decrease of DHBV DNA in serum was observed. Therefore, it was investigated if FLT could be efficiently phosphorylated in duck liver.

From DHBV-infected and non-infected duck livers protein extracts were prepared and partially purified by ion-exchange chromatography. Only one enzyme with thymidine (and deoxycytidine) kinase activity was found, corresponding to thymidine kinase 2 (i.e. the mitochondrial type of deoxynucleoside kinase). In contrast to extracts from duck spleen, the liver extracts showed a very low capacity to phosphorylate FLT, and this may explain the failure of FLT to prevent DHBV replication in vivo. These results suggest that new nucleoside analogues designed for treatment of hepatitis B should be evaluated with respect to phosphorylation by enzymes from non-dividing liver cells.
Pharmacokinetics of 3′-azido-2′,3′-dideoxy-5-methylcytidine in Rats
Authors: Boudinot F. D. , Ibrahim S. S. , Qin Y. , Chu C. K. , Schinazi R. F.
Published: May 2015

3′-Azido-2′,3′-dideoxy-5-methylcytidine (AzddMeC) has been shown to have potent activity against human immunodeficiency virus (HIV) in vitro. The purpose of this study was to characterize the pharmacokinetics of AzddMeC in rats. AzddMeC was administered intravenously at doses of 10, 50 and 100 mg kg−1. Plasma and urine AzddMeC concentrations were determined by HPLC. Pharmacokinetic parameters were generated by area/moment analysis. Plasma AzddMeC concentrations after 10mg kg−1 were too low to accurately calculate pharmacokinetic parameters. Following 50 and 100mg kg−1 AzddMeC, plasma drug concentrations declined rapidly with a terminal half-life of approximately 2.5 h. No statistically significant differences were noted in pharmacokinetic parameters between the two higher doses. Total clearance was 1.57 ± 0.33 (mean ± SD) and 1.76 ± 0.32I h−1 kg−1 after 50 and 100 mg kg−1 AzddMeC, respectively. Renal excretion accounted for approximately half of total clearance with 55 ± 11% of the dose recovered as unchanged drug in urine. AzddMeC was not metabolized by deamination to AZT in the rat. No glucuronide metabolite was found in urine. Steady-state volume of distribution of AzddMeC averaged 1.73 ± 0.78 and 1.46 ± 0.441 kg−1 following 50 and 100 mg kg−1, respectively. Thus, the disposition of AzddMeC in rats is independent of dose over the range of 50–100 mg kg−1. The pharmacokinetics of AzddMeC in rats are similar to those of 2′,3′-dideoxycytidine, while the clearance of AzddMeC is 40% less than that of 3′-azido-3′-deoxythymidine.
Novel Sensitivity of Acyclovir-Resistant Varicella–Zoster Virus to Anti-Herpetic Drugs
Authors: Shiraki K. , Namazue J. , Okuno T. , Yamanishi K. , Takahashi M.
Published: May 2015

Acyclovir-resistant varicella–zoster virus (VZV) selected in the presence of acyclovir was 3–20 times more sensitive to nucleoside analogues with arabinosyl configuration than the parent virus. Their sensitivity in comparison with a thymidine kinase-deficient mutant to anti-herpetic drugs and sensitivity to phosphonoacetic acid suggested that recognition by altered mutants' DNA polymerase might result in their novel sensitivity to nucleoside analogues. Information on the unique sensitivity of these acyclovir-resistant mutants may be useful in designing chemotherapeutic agents against VZV.
Targets for Antiviral Chemotherapy: Herpes Simplex Virus Regulatory Protein, Vmw65
Authors: O'Hare P.
Published: May 2015

The virion protein, Vmw65, of herpes simplex virus selectively induces the transcription of the virus immediate–early genes and is required for normal virus replication and for virulence in animal models. Vmw65 operates by interacting with a host cell transcription factor (Oct-1) and analysis of the structure/function relationship within Vmw65 has facilitated the design of a peptide, corresponding to a local domain of the protein, which interferes with the Vmw65–Oct-1 interaction. The selective interference of protein–protein interactions involved in gene regulation may provide a suitable target for the inhibition of virus replication.
Mechanism of Selective Inhibition of Herpes Simplex Virus Replication by Deoxycytidine Analogues: Interaction of 5-methoxymethyl-2′-deoxycytidine-5′-triphosphate with DNA Polymerases
Authors: Aduma P. J. , Gupta S. V. , Allaudeen H. S. , Stuart A. L. , Tourigny G.
Published: May 2015

5-Methoxymethyl-2′-deoxycytidine (MMdCyd) is a selective anti-herpes agent that is dependent upon initial activation by herpes simplex virus (HSV)-induced deoxythymidine/deoxycytidine kinase. 5-Methoxymethyl-2′-deoxycytidine triphosphate (MMdCTP) was synthesized. The nature of the interaction of MMdCTP and dCTP with the DNA polymerase of Escherichia coli, HSV-1 and human DNA polymerase α was determined using specific and optimized assay conditions for each enzyme. MMdCTP was a better substrate for HSV-1 DNA polymerase compared to dCTP. At a nucleotide concentration of 10 μm MMdCTP utilization was 130% that of an equimolar concentration of dCTP. Under similar conditions, human DNA polymerase α utilized MMdCTP about as efficiently as dCTP. E. coli DNA polymerase I preferentially utilized dCTP. The IC50 values of MMdCTP were 8 × 10−7 m and 29 × 10−7 m for HSV-1 and human α DNA polymerase, respectively. MMdCTP is a competitive inhibitor of HSV-1 DNA polymerase with respect to dCTP incorporation ( Ki = 3.8 × 10−7 m). Preferential utilization of MMdCTP and its eventual incorporation into HSV DNA seems to account for the antiviral action of MMdCyd.
A Study of the Efficacy of the Immunomodulatory Compound 7-thia-8-oxoguanosine in Coronavirus 229E Infections in Human Volunteers
Authors: Higgins P. G. , Barrow G. I. , Tyrrell D. A. J. , Snell N. J. C. , Jones K. , Jolley W. B.
Published: May 2015

Intranasal 7-thia-8-oxoguanosine (NARI 10146) compared with placebo had no influence on the course of experimental coronavirus 229E infections in human volunteers. Possible reasons are discussed for the failure to confirm successful rodent experiments in man.
Antiviral Activity of low-MW Dextran Sulphate (Derived from dextran MW 1000) Compared to Dextran Sulphate Samples of Higher MW
Authors: Witvrouw M. , Schols D. , Andrei G. , Snoeck R. , Hosoya M. , Pauwels R. , Balzarini J. , De Clercq E.
Published: May 2015

Dextran sulphate inhibits the replication of enveloped viruses (such as retro-, herpes-, toga, arena-, rhabdo-, orthomyxo- and paramyxoviruses), but is inactive against non-enveloped viruses (such as polio, Coxsackie and reovirus). Within the molecular weight (MW) range of 10000–50000, not much variation was observed in the antiviral potencies of different dextran sulphate (DS) samples, irrespective of the virus examined. However, in contrast with the higher MW samples, the low MW DS sample (prepared from dextran with a MW of 1000) was virtually inactive against herpes simplex virus type 1 and type 2, vesicular stomatitis virus, vaccinia virus, influenza A virus, respiratory syncytial virus and togaviruses (Sindbis, Semliki Forest). It was 10–20-fold less active than the higher MW samples against cytomegalovirus and arenaviruses (Junin, Tacaribe). The inhibitory potency of the 1000 MW DS sample against human immunodeficiency virus (HIV) varied considerably depending on the virus strain and cell type. When examined in MT-4 cells, the 1000 MW DS sample was 7000-, 1000-, 200- or 10-fold more inhibitory to HIV-1HE than HIV-2EHO, HTLV-IIIB, HTLV-IIIRF and LAV-2ROD, respectively. In CEM cells, however, HIV-1HE was less sensitive to the inhibitory effect of the 1000 MW DS sample than HIV-2EHO, equally sensitive as HTLV-IIIB and fivefold more sensitive than LAV-2ROD.
Naphthalenesulphonic Acid Derivatives as Potential anti-HIV-1 Agents. Chemistry, Biology and Molecular Modelling of Their Inhibition of Reverse Transcriptase
Authors: Mohan P. , Hopfinger A. J. , Baba M.
Published: May 2015

Activity against human immunodeficiency virus (HIV) in the naphthalenesulphonic acid series is most pronounced in the disulphonic acid series. In this class of compounds, N-acyl derivatives of 4-amino-5-hydroxy-2,7-naphthalenedisulphonic acid demonstrate significant anti-HIV activity at non-toxic doses. The most potent compounds in this group of agents are bis naphthalenedisulphonic acids. A bis derivative containing a decamethylene spacer demonstrated activity against HIV-1, HIV-2 giant cell formation and reverse transcriptase (RT). This compound also demonstrated an in vitro therapeutic index (ratio of 50% cytotoxic concentration to 50% inhibitory antiviral concentration) of 10.6. Molecular modelling analyses of this agent, suramin, and several suramin analogues were undertaken to explain the potent anti-HIV-1 RT activity. These studies were carried out using the molecular decomposition/recomposition strategy, conformational searching, energy minimization and molecular dynamics (MD) simulation. The bis naphthalenedisulphonic acid derivative compound 1, having a flexible decamethylene spacer, was shown to be able to mimic the helical twist of the B-DNA backbone as a low energy conformer state.
Inhibitory Effects of Polycations on the Replication of Enveloped Viruses (HIV, HSV, CMV, RSV, Influenza A Virus and Togaviruses) in vitro
Authors: Hosoya M. , Neyts J. , Yamamoto N. , Schols D. , Smoeck R. , Pauwels R. , De Clercq E.
Published: May 2015

Polycationic compounds, i.e. poly-l-lysines and poly-d-lysines, were evaluated for their in vitro effect on the replication of various viruses. Poly-l-lysines of different molecular weight proved inhibitory to the replication of several enveloped viruses, such as human immunodeficiency virus type 1 and type 2 (HIV-1 and HIV-2), respiratory syncytial virus (RSV), influenza A virus, Sindbis virus, Semliki Forest virus, vesicular stomatitis virus (VSV), herpes simplex virus type 1 (HSV-1) and human cytomegalovirus (CMV). The mechanism of action of the polylysines against HIV-1, RSV and CMV could be attributed to an inhibitory effect on virus binding to the host cells, as demonstrated by an indirect immunofluorescence/laser flow cytofluorographic method, virus plaque reduction and measurement of radiolabelled virion association with the cells, respectively.
Anti-HIV Activities of Novel Nucleoside Analogues: Acyclic and Tricyclic Base Nucleosides
Authors: Clayette P. , Merrouche Y. , Gharbaoui T. , Roques P. , Lechevallier A. , Beugelmans R. , Olomucki M. , Dormont D.
Published: May 2015

Two series of new nucleoside derivatives, acyclic nucleosides and tricyclic base nucleosides, were screened for cellular toxicity and against HIV-1. Compounds were tested on MT4, MT2, U937 cell lines and PBMCs in multiwell tissue culture plates. Cells were infected in vitro with 2 TCID50/105 cells or 0.2 TCID50/105 cells of HIV-1-LAV-1. Two out of eight tricyclic derivatives showed little cytotoxicity; at 100μM, only two acyclic compounds exhibited cellular toxicity in U937 cells. In vitro, none of these 19 compounds demonstrated any efficient activity against the lentiviral HIV infection and replication. Furthermore, combinations of these acyclonucleosides with ddC or AZT did not inhibit HIV-1-LAV-1 replication additively or synergistically. Because acyclonucleosides did not induce any cytotoxic effect, other compounds of this family should be investigated.
Improved Delivery through Biological Membranes. Synthesis and Antiviral Activity of a Series of Ribavirin Chemical Delivery Systems: 2′ and 3′ Derivatives
Authors: Deyrup M. , Sidwell R. , Little R. , Druzgala P. , Bodor N. , Brewster M. E.
Published: May 2015

Ribavirin was chemically manipulated to provide a number of derivatives in which a 1,4-dihydrotrigonellinate species was attached to either the 2′ or 3′-position. In addition, a variety of other modifications was used to augment the lipophilicity and stability of the ribavirin redox systems. Prepared compounds were tested in a murine model of viral encephalitis. Intravenous administration of an isomeric pair of derivatives (1-[3′-O-(N-methyl-3-carbonyl-1,4-dihydropyridine)-2′-O-benzoyl-β-D-ribofuranosyl]-1,2,4-triazole-3-carboxamide/1-[2′-O-(N-methyl-3-carbonyl-1,4-dihydropyridine)-3′-O-benzoyl-β-D-ribofuranosyl]-1,2,4-triazole-3-carboxamide) resulted in 43% survival compared with 0% for vehicle treatment and resulted in a decrease in brain viral titres by 10-fold.
Effects of Penciclovir and Famciclovir in a Murine Model of Encephalitis Induced by Intranasal Inoculation of Herpes Simplex Virus Type 1
Authors: Goldthorpe S. E. , Boyd M. R. , Field H. J.
Published: May 2015

Mice inoculated intranasally with a potentially lethal dose of HSV-1 (strain SC16) were used to evaluate the efficacy of penciclovir (PCV) and its oral form, famciclovir (FCV) in the treatment of acute herpes encephalitis. In a comparative experiment, orally administered PCV was less effective than ganciclovir (GCV) in reducing mortality of infected mice, but was of similar effectivenss to acyclovir (ACV), Late deaths from ongoing infections were observed following cessation of treatment with both ACV and FCV. Delaying the onset of treatment by more than 1 day post infection markedly reduced the ability of orally administered ACV, PCV, and FCV to prevent death. Treatment from day 1 with FCV administered ad libitum in the drinking water resulted in rapid clearance of infectious virus from all parts of the brain, but latent virus was detected by Southern blot hybridization in the peripheral and central nervous system of survivors 1 month post infection. In untreated mice, infectious virus was also detected in the epithelium of the turbinate bones and in the lungs from 1 day after intranasal inoculation, and acute inflammatory changes were seen in the lungs. FCV was more effective in clearing virus from the lungs than from the turbinate bones in these mice. These data, concerning the importance of virus replication in the respiratory tract with regard to subsequent encephalitis, are considered to be a novel aspect of this study.
Inhibition of gp120 Binding to the CD4 Antigen by Dyes: Mechanism of Effect and Contribution to anti-HIV Activity
Authors: Kozlowski M. R. , Watson A.
Published: May 2015

Several compounds developed for use as dyes have shown activity against HIV-1. The present study examines one putative mechanism of this anti-HIV activity, inhibition of gp120/CD4 binding, and its contribution to the antiviral effects of three chemical classes of dyes. Although, for most dyes, the ability to inhibit gp120/CD4 binding and the reported anti-HIV activities do not correlate, a group of dyes is identified whose anti-HIV activity does appear to be related to binding inhibition. Qualitative examination of the effect of two of these dyes on the gp120/CD4 binding isotherm suggests that the inhibition is non-competitive. Dyes which act by preventing viral binding may represent prototypes for the development of novel drugs for the treatment or prevention of AIDS.
Stability of Carbovir, a Potent Inhibitor of HIV, to Phosphorolysis by Human Purine Nucleoside Phosphorylase
Authors: Marr C. L. P. , Penn C. R.
Published: May 2015

Carbovir, a carbocyclic guanosine analogue, is a selective and potent inhibitor of HIV-1 in vitro. The (-)enantiomer of carbovir has been shown, by spectrophotometric and high pressure liquid chromatography (HPLC) analysis, to be stable to phosphorolytic cleavage by purified human erythrocytic purine nucleoside Phosphorylase. Thus depurination, and the salvage reaction via hypoxanthine-guanine phosphoribosyl transferase, would be unlikely to be involved in the metabolism of carbovir. Inhibition of purine nucleoside Phosphorylase interferes with T-lymphocytic function and would be an undesirable activity for any potential antiviral agent. The present study also showed that carbovir, at concentrations up to 300 μM, did not inhibit purine nucleoside Phosphorylase.