bluuebunny/crossref_metadata_2025 huggingface dataset:
Mechanical and degradation properties of successive alkali treated completely biodegradable sisal fiber reinforced poly lactic acid composites
Authors: Rajesh Gunti , Prasad AV Ratna , Gupta AVSSKS
Published: May 2015

The natural fiber reinforced biodegradable polymer composites were prepared with short sisal fiber as reinforcement in poly lactic acid (PLA) matrix. The sisal fiber is treated with 10% NaOH followed by H2O2. The composites were prepared with untreated and treated short sisal fibers at different weight proportions up to 25% in PLA matrix and investigated for mechanical and degradation properties. The results showed that the composite with treated fiber at 20% fiber loading has shown 30% and 8% higher tensile strength than neat PLA and untreated sisal/PLA composite, respectively. The flexural strength of treated sisal fiber composite at same weight fraction was 17% higher than that of plain PLA. The impact strength of composite with untreated fibers at 25% fiber loading was 107% high compared to that of neat PLA whereas the impact strength of treated sisal composite was reduced with increased fiber loading. The water absorption was high for untreated sisal/PLA composite compared to all other composites in the present study. Untreated sisal/PLA composite has high thermal degradation temperature compared to composite with treated fibers but lower than that of pure PLA. The enzymatic environment has increased the rate of degradation of composites. Surface morphology of tensile fractured and soil degraded surfaces of the composites were observed using scanning electron microscopy.
Antepartum Mastitis
Authors: Malik Sushma , Patil Varsha Anant , Korday Charusheela Sujit , Shah Dipti Parag
Published: May 2015

Puerperal or lactational mastitis is an inflammatory condition of the breast that is commonly encountered in breastfeeding mothers. It occurs most commonly in the postpartum period, generally in the first 6 weeks of breastfeeding. In contrast, antepartum mastitis is an uncommon condition, and if not treated adequately, it may be complicated by the formation of a breast abscess. The authors present a case of a 24-year-old, second gravida mother who developed unilateral antepartum mastitis with abscess formation at 34 weeks of gestation, which was initially treated with antibiotics and surgical drainage. However, her symptoms persisted over the next 2 weeks, and she was referred to the authors’ institution, where she was managed with antibiotics and surgical drainage after delivering a healthy near-term infant. The abscesses healed completely 2 months later, with sequelae of residual scarring and a nonprotractile nipple. The authors wish to emphasize that health care providers should be aware of the occurrence of mastitis in the antepartum period. Early recognition with adequate treatment of mastitis is the key to avoiding complications, and this will prevent lactation issues and also reduce morbidity in the mother and neonate.
Does Neighborhood Disorder Predict Recovery From Mobility Limitation? Findings From the Health and Retirement Study
Authors: Latham Kenzie , Williams Monica M.
Published: May 2015

Objective: This research explores whether perceptions of physical neighborhood disorder predict recovery from mobility limitation over a 2-year period and examines whether psychosocial factors (i.e., depressive symptomology and mastery) and physical activity are salient mediators. Method: Using data from the Health and Retirement Study (HRS): Participant Lifestyle Questionnaire (2008-2010), odds ratio estimates of recovery were ascertained using binary logistic regression, and post hoc Sobel tests were conducted to formally assess mediation. Results: Net of demographic characteristics and socioeconomic status, increased neighborhood disorder was associated with lower odds of recovery. However, both psychosocial indicators and physical activity were significant individual partial mediators, which suggest neighborhood disorder influences recovery from physical impairment via psychosocial processes and barriers to physical activity. Discussion: Reducing neighborhood disorder may enhance older residents’ psychosocial well-being and improve participation in physical activity, thus increasing recovery from mobility limitation and preventing subsequent disability.
Synthesis of Some Novel Dialkyl Phosphate Derivatives of 3′-Modified Nucleosides as Potential Anti-AIDS Drugs
Authors: McGuigan C. , Nicholls S. R. , O'Connor T. J. , Kinchington D.
Published: May 2015

The reaction of thymidine with diethyl, dipropyl, and dibutyl phosphorochloridates yields novel 5′-(dialkyl phosphates), characterized by spectroscopic and analytical data. These are readily mesylated at the 3′-position. Similar reaction of 3′- O-acetyl and 3′- O-ethyl thymidine with dialkyl phosphorochloridates gives an analogous series of compounds. Lastly, reaction of the anti-AIDS drug AZT with these phosphorylating agents gives the corresponding 3′-azido products. It was hoped that these might act as membrane-soluble pro-drugs of the bio-active free nucleotides of AZT and that the alternative 3′-substituents might also confer similar activity. In fact, none of the compounds studied displayed any anti-HIV activity in vitro. This is attributed to the metabolic stability of the trialkyl phosphate moiety.
Sulphated Sugar Alpha-Cyclodextrin Sulphate, a Uniquely Potent Anti-HIV Agent, Also Exhibits Marked Synergism with AZT, and Lymphoproliferative Activity
Authors: Anand R. , Nayyar S. , Pitha J. , Merril C. R.
Published: May 2015

Sulphated sugars, alpha-cyclodextrin sulphate (A-CDS), sodium pentosan polysulphate (PPS), and beta-cyclodextrin sulphate (B-CDS) were evaluated for their inhibitory effect on the replication of human immunodeficiency virus (HIV-1) in normal human peripheral blood mononuclear cells (PMNCs). All three drugs had potent anti-HIV activity, A-CDS being the most potent. A-CDS, PPS and B-CDS were also tested for their direct inhibitory effect on reverse transcriptase (RT) in vitro. PPS inhibited the RT reaction at 4.0 μg ml−1 and above whereas B-CDS and A-CDS did not. The drugs were not cytotoxic up to 100 μg ml−1 and also showed significant lymphoproliferative activities. PPS and B-CDS exhibited higher lymphoproliferative activity than A-CDS. A-CDS, B-CDS, and PPS showed profound antiviral synergism with AZT. An additive anti-HIV effect, rather than a synergestic effect, was observed between the sulphated sugars. Thus, these sulphated sugars, because of their nontoxic nature, lymphoproliferative activity and anti-HIV activity at low concentrations, may be valuable chemotherapeutic agents in the treatment of AIDS. In particular, A-CDS, because of its marked anti-HIV synergism with AZT (which would lower the required dose of AZT in vivo), could result in an efficacious and essentially nontoxic combination chemotherapy for AIDS.
Synthesis and Evaluation of Some Novel Phosphoramidate Derivatives of 3′-Azido-3′-Deoxythymidine (AZT) as Anti-HIV Compounds
Authors: McGuigan C. , Devine K. G. , O'Connor T. J. , Galpin S. A. , Jeffries D. J. , Kinchington D.
Published: May 2015

A series of monophosphate triester derivatives of 3′-azido-3′-deoxythymidine (AZT), designed as membrane-soluble pro-drugs of the nucleotide (AZTMP), have been tested for activity against the human immunodeficiency virus (HIV-1). It has been found that when carboxyl-protected, amino-linked amino acids, and alkyl chains, are asymmetrically substituted on the 5′-phosphate a significant antiviral effect is observed. Moreover, the activity of the compounds is profoundly dependent on the structure of the phosphate moiety, and in particular on the nature of the amino acid.
Antiviral Activity of Mixtures of Compounds against Herpesviruses
Authors: Al-Nisairawi L. A. T. , Guadagnin V. , Jennings R. , Potter C. W.
Published: May 2015

A simple method for investigating the antiviral activity of mixtures of two antiviral compounds against herpes simplex virus (HSV) is described; the technique involves a modification of the dye-uptake technique for measuring antiviral activity, and the results are analysed by two methods for evidence of synergy or additive or antagonist effects. The antiviral activity of combinations of four antiviral compounds against HSV-1 and HSV-2 were investigated. The results indicate that interferon-alpha (IFN-α) with acyclovir or ara-A shows synergy, but IFN-α with ribavirin shows an additive effect. Ribavirin shows no synergism with any of the three compounds tested, and ara-A shows marginal synergy with acyclovir. The pattern of these results does not allow any prediction of which mixtures may show synergy. With the present limited number of antiviral compounds, all new combinations should be tested; and these further results may allow future predictions.
In vitro Antiviral Activity and Cytotoxicity of Aspirin: Lack of Selective Activity against Influenza a Virus or Rhinovirus
Authors: Crump C. E. , Rollins B. S. , Hayden F. G.
Published: May 2015

Because of a report that aspirin 5–10 mm has potent anti-influenza virus A activity in vitro, we assessed aspirin's cellular cytotoxicity and inhibitory effects for influenza A and rhinovirus in cell culture. Aspirin 5-1 mm was inhibitory for the growth of uninfected rhesus monkey kidney, MDCK, MRC-5 strain human embryonic lung, and HeLa cells. Concentrations of 2.5 mm and lower had no inhibitory affects for growth of representative influenza A strains in MDCK or RMK cells or for rhinovirus serotype 39 or 1A in MRC-5 and HeLa cells. In summary, our in vitro studies did not find evidence for selective anti-rhinovirus or influenza A virus activities at non-cytotoxic concentrations of aspirin.
Sulphated Polymers are Potent and Selective Inhibitors of Various Enveloped Viruses, Including Herpes Simplex Virus, Cytomegalovirus, Vesicular Stomatitis Virus, Respiratory Syncytial Virus, and Toga-, Arena- and Retroviruses
Authors: Schols D. , De Clercq E. , Balzarini J. , Baba M. , Witvrouw M. , Hosoya M. , Andrei G. , Snoeck R. , Neyts J. , Pauwels R. , Nagy M. , Györgyi-Edelényi J. , Machovich R. , Horváth I. , Low M. , Görög S.
Published: May 2015

The sulphated polymers, such as polyvinylalcohol sulphate (PVAS) and its co-polymer with acrylic acid (PAVAS), have proved to be potent inhibitors for herpes simplex virus, human cytomegalovirus, vesicular stomatitis virus, respiratory syncytial virus, Sindbis virus, Semliki Forest virus, Junin virus, Tacaribe virus, murine sarcoma virus and human immunodeficiency virus. They are not inhibitory to non-enveloped viruses, such as poliovirus and reovirus. The broad-spectrum antiviral effects of these compounds depend on their molecular weight and degree of sulphation. Pharmacokinetic studies in rabbits have indicated that after intravenous bolus injection the serum concentrations of these compounds decay biphasically, with an initial half-life of approximately 90–120 min.
A Comparison of Pyrimidinone Analogue Immunomodulators for Treatment of Phlebovirus Infections in Mice
Authors: Sidwell R. W. , Huffman J. H. , Coombs J. , Renis H. , Huggins J. , Kende M.
Published: May 2015

The substituted pyrimidinone immunomodulators 5-bromo-2,3-dihydro-2-imino-6-phenyl-4(1H)-pyrimidinone (ABPP), 5-iodo-2,3-dihydro-2-imino-6-phenyl-4(1H)-pyrimidinone (AIPP), 5-bromo-2,3-dihydro-2-imino-6-methyl-4(1H)-pyrimidinone (ABMP), 5-chloro-2,3-dihydro-2-imino-6-phenyl-4(1H)-pyrimidinone (ACPP), 5-bromo-2,3-dihydro-2-iminp-6-(3-fluorophenyl)-4(1H)-pyrimidinone (ABmFPP) and 5-chloro-2,3-dihydro-2-imino-6-(2,3-difluorophenyl)-4(1H)-pyrimidinone (AComF2PP) were evaluated against the hepatotropic and immunosuppressive infection of mice induced by Punta Toro virus, a Phlebovirus related to Rift Valley fever virus. Using intraperitoneal (i.p.) treatments once daily for 3 days beginning 1 day prior to virus exposure, the order of efficacy was ABPP > ABmFPP > AComF2PP > AIPP > ABMP > ACPP, with prevention of death as end-point. Using single i.p. treatment 1 day prior to virus exposure, antiviral activity was seen in the order ABPP > ABmFPP > ABMP > AIPP > ACPP > AComF2PP. Three active pyrimidonones, ABPP, ABMP and AIPP, were given by gavage (p.o.) using the above 3-day treatment schedule. In this experiment, expanded parameters were used, with prevention of death seen as well as decreased hepatic icterus, as evidenced by lowered liver scores and serum glutamic oxalacetic and pyruvic transaminases. In addition, recoverable virus titres were reduced in the livers and sera of the mice. Greatest activity was seen using ABPP, followed by ABMP and then by AIPP. ABPP in doses of 100–800 mg kg−1 was markedly effective when administered p.o. in single treatments given as late as 24 hr after virus inoculation; a single dose, 400 mg kg−1, prevented death when given as late as 48 hr after virus exposure. In comparison of three once-daily, every-other-day, or every 2-day p.o. treatments, ABPP was most effective using the every-other-day regimen.
Ketamine-Mediated Inhibition of Rabies Virus Infection in vitro and in Rat Brain
Authors: Lockhart B. P. , Tsiang H. , Ceccaldi P. E. , Guillemer S.
Published: May 2015

This report describes the effect of the dissociative anaesthetic ketamine, a non-competitive antagonist of the N-methyl-d-aspartate (NMDA) receptor, on the infectivity of the neurotropic rabies virus, in neuronal culture systems and in vivo. Ketamine (1–2 mm) produced an approximate 100–1000-fold decrease in the production of rabies virus in neuronal cell cultures. Rabies virus infection was also inhibited in non-neuronal cell lines (Baby Hamster Kidney fibroblasts) but the inhibitory effects appeared better expressed in cells of neuronal origin (neuroblastoma and primary neuronal cultures). The kainate/quisqualate competitive antagonist CNQX did not modify the course of rabies virus infection and modulators of known NMDA regulatory sites (Mg2+, Zn2+, HA-966) failed to antagonize the ketamine-mediated inhibition of rabies virus production in neuroblastoma cells. Furthermore, Ca2+-mobilization does not appear to be involved because Ca2+-depleted and EGTA-treated medium did not affect the normal production of rabies virus. The action of ketamine on rabies virus infection in vivo was also investigated; peripheral treatment of rats with this drug inhibited rabies virus infection in the thalamus, cortex and hippocampal formation (in particular the pyramidal layer of the CA1 region). Taken together, these data suggest that the ketamine-mediated inhibition of rabies virus production in vitro, although highly selective, is not acting via classic NMDA receptor-mediated mechanisms. However, the ketamine-mediated retardation of rabies virus infection in vivo may offer new prospects for post-exposure rabies antiviral therapy.
3′-Substituted Thymine α-L-nucleoside Derivatives as Potential Antiviral Agents: Synthesis and Biological Evaluation
Authors: Génu-Dellac C. , Gosselin G. , Aubertin A.-M. , Obert G. , Kirn A. , Imbach J.-L.
Published: May 2015

Hitherto unknown 1-(3-deoxy-3-substituted-α-L-lyxofuranosyl)thymines and their 2-deoxy derivatives related to azidothymidine (AZT) and its congeners have been synthesized and their antiviral properties examined. They were prepared by nucleophilic substitution with inversion of configuration from 3′-O-trifluoromethanesulphonate α-L-arabinofuranonucleosides and their 2′-deoxy derivatives. All the prepared compounds were tested for their activity against a variety of RNA and DNA viruses, but they did not show significant antiviral activity.
Combination Chemotherapy of Punta Toro Virus Infections in Mice Using Ribavirin and 7-thia-8-oxoguanosine
Authors: Smee D. F. , Coombs J. , Huffman J. H. , Huggins J. W. , Sidwell R. W.
Published: May 2015

Ribavirin was combined with the immunoenhancing agent 7-thia-8-oxoguanosine (TOGuo) to treat lethal experimental Punta Toro virus infections in mice. Lethal hepatic disease caused by the Adames strain of the virus was treated orally with ribavirin and intraperitoneally with TOGuo, with both treatments starting 24 h after virus inoculation. By themselves, ribavirin (25 mg/kg) and TOGuo (12.5 and 25 mg/kg) protected 80–100% of mice from mortality, but lower doses of each were ineffective. Combinations of the two agents (ribavirin, 25 mg/kg plus TOGuo at 6.25 and 12.5 mg/kg) produced synergistic decreases in hepatic icterus scores, liver and spleen virus titres, and serum alanine aminotransferase and aspartate aminotransferase activities. Lower dosage combinations were not synergistic. Of particular interest was the observation that TOGuo (25 mg/kg) could reverse the lethal toxicity of a high dose of ribavirin (1250 mg/kg) both in Punta Toro virus-infected and uninfected mice. These data suggest that TOGuo increased the therapeutic index of ribavirin by decreasing toxicity and increasing antiviral activity in this model.
Acyclovir Treatment Stimulates dCMP Deaminase Activity in HSV-1-Infected Cells
Authors: Karlsson A.
Published: May 2015

Herpes simplex virus (HSV) infection induces enzymes involved in DNA precursor metabolism and DNA synthesis. The level of the DNA precursors dCTP, dTTP and dGTP increases after HSV infection, while the dATP level decreases. Inhibition of viral DNA synthesis by acyclovir (ACV) increases all four deoxyribonucleoside triphosphate levels, in particular that of dTTP. In the present work the dynamics of metabolism of pyrimidine deoxyribonucleotides and changes in the dTTP and dCTP pools in HSV-1-infected HL cells and in infected cells where viral DNA synthesis was inhibited by ACV were studied. In the absence of the drug the major part of the dCDP synthesized was incorporated into DNA. ACV treatment inhibited DNA synthesis completely but increased de novo dTMP synthesis. A continued ribonucleotide reductase activity in ACV-treated HSV-1-infected cells contributes to the increasing dTTP pool. The allosteric regulation of dCMP deaminase activity in HSV-1-infected cells was investigated. The great increase of de novo dTMP synthesis was shown to be due to stimulation of dCMP deaminase activity by an increasing dCTP pool. The high dTTP pool is suggested to be of secondary importance to the dCTP pool in the regulation of dCMP deaminase activity in HSV-1-infected cells.
Failure of Castanospermine to Reduce Spleen or Serum Virus Titres in Rauscher Murine Leukaemia Virus-Infected Mice
Authors: Hollingshead M. G. , Westbrook L. , Toyer B. J. , Allen L. B.
Published: May 2015

The effects of orally administered castanospermine (CS) and azidothymidine (AZT) on spleen and serum virus titres and on spleen weights of mice inoculated with Rauscher murine leukaemia virus (R MuLV) were evaluated. Virus titres of samples from CS-treated mice did not differ appreciably from saline-treated mice, despite a significant inhibition of splenomegaly. In contrast, AZT treatment resulted in significant inhibition of splenomegaly and a reduction of virus titres.
Antiviral Activity against VZV and HSV Type 1 and Type 2 of the (+) and (−) Enantiomers of (R,S)-9-[4-hydroxy-2-(hydroxymethyl)butyl]guanine, in Comparison to other Closely Related Acyclic Nucleosides
Authors: Abele G. , Cox S. , Bergman S. , Lindborg B. , Vissgården A. , Karlström A. , Harmenberg J. , Wahren B.
Published: May 2015

The separate (+) and (−) enantiomers of the acyclic guanosine analogue 9-[4-hydroxy-2-(hydroxymethyl)-butyl]guanine (2HM-HBG) were tested for inhibition of varicella-zoster virus (VZV), herpes simplex virus type 1 (HSV-1) and herpes simplex virus type 2 (HSV-2). In all cases the (−) enantiomer was the most active enantiomer. The (+) enantiomer was 10 times less active than the racemate against VZV and inactive against HSV-1 and -2.

The parent compound, 9-(4-hydroxybutyl)guanine, containing an unbranched side chain, was inactive against VZV, whereas substitution with a hydroxymethyl group at the 2 or 3 position of the side chain conferred anti-VZV activity. The effect of hydroxymethyl substitution may increase the recognition of the compound by the VZV thymidine kinase by increasing its similarity to the natural substrate thymidine. Further substitution of the side chain of the parent compound with oxygen, fluorine or hydroxyl groups did not confer antiviral activity against VZV.

Two VZV strains were isolated which could be grown in the presence of high concentrations of 2HM-HBG and which were also cross-resistant to other nucleoside analogues. These strains induced very little viral thymidine kinase activity in infected cells and thus were probably deficient for a functional thymidine kinase.

2HM-HBG exhibited a persistent antiviral effect even after the nucleoside was removed from the medium of VZV-infected cells, whereas acyclovir did not show this effect.
Effects of a Specific Inhibitor of HIV Proteinase (Ro 31-8959) on Virus Maturation in a Chronically Infected Promonocytic Cell Line (U1)
Authors: Craig J. C. , Grief C. , Mills J. S. , Hockley D. , Duncan I. B. , Roberts N. A.
Published: May 2015

The human immunodeficiency virus (HIV) proteinase inhibitor Ro 31-8959 prevents the maturation of virus in phorbol 12-myristate 13-acetate (PMA)-stimulated U1 cells, a chronically infected promonocytic cell line. Inhibition of both the morphological maturation of virions and the enzymic processing of gag polyprotein (p56) to produce capsid protein p24 was demonstrated at nanomolar concentrations of the compound. Furthermore, prolonged inhibition of the processing of p56 antigen was confirmed in pulse-chase experiments. The conclusion is that Ro 31-8959 can inhibit production of mature virions in a promonocyte cell line which is infected chronically/latently with HIV.
Inhibition of Hepatitis B Virus DNA Polymerase by Thymidine Triphosphate Analogues in vitro
Authors: Reimer K. , Matthes E. , Janta-Lipinski M. v. , Meisel H.
Published: May 2015

A series of thymidine triphosphate analogues was tested for effect inhibitory on DNA polymerase activity in isolated hepatitis B virus (HBV) particles. The most efficient compounds were 2′,3′-dideoxy-3′-fluoro-5-vinyluridine triphosphate [50% inhibititory dose (ID50) = 0.25 μm], 2′,3′-dideoxy-3′-fluoro-5-bromovinyluridine triphosphate (ID50 = 0.80 μm), 2′,3′-dideoxy-3′-fluoro-4-thiothymidine triphosphate (ID50 = 0.80 μm) and 2′,3′-dideoxy-3′-fluoro-5-bromouridine triphosphate (ID50 = 1.00 μm). The inhibitors only moderately influenced the cellular DNA polymerase α (ID50 ranging from 10 μm to 140 μm) but had a noteworthy effect on DNA polymerase β (ID50 ranging from 0.8 μm to 7.0 μm), which could be associated with toxicity and mutagenicity in human cells. Kinetic analysis revealed a competitive type of inhibition for the most efficient compound, fluoro-5-vinyluridine triphosphate. The inhibition constant ( Ki) was estimated to be 0.25 μm compared with a Michaelis constant ( Km) value of about 0.4 μm for the substrate.
Herpes Simplex Virus Isolates from an Immunocompromised Patient who Failed to Respond to Acyclovir Treatment Express Thymidine Kinase with Altered Substrate Specificity
Authors: Nugier F. , Collins P. , Larder B. A. , Langlois M. , Aymard M. , Darby G.
Published: May 2015

Ten sequential post-treatment herpes simplex virus type 1 (HSV-1) isolates were obtained from an immunocompromised patient whose infection, during prolonged treatment, became unresponsive to acyclovir (ACV). Of the ten isolates, eight later isolates were resistant in vitro to ACV and ganciclovir (DHPG), but remained sensitive to 9-β-D-arabinofuranosyladenine (ara-A) and phosphonoformate (PFA). Biochemical characterization of plaque-purified clones of the resistant isolates revealed an altered thymidine kinase (TK) substrate specificity phenotype. The comparative nucleotide sequence analysis of polymerase chain reaction (PCR)-amplified DNA encoding the TK genes of one sensitive and two resistant clones showed a single mutation at nucleotide 527. This change would result in a substitution of arginine by glutamine at residue 176 of the polypeptide, a mutation previously observed in a laboratory isolated variant, SC16 Tr7 (Darby et al., 1986).
Relationship between Conformation and Antiviral Activity-II. 5-Methoxymethyl-2′-deoxycytidine and 5-methoxymethyl-N4-methyl-2′-deoxycytidine
Authors: Gupta V. S. , Aduma P. J. , Jia Z. , Stuart A. L. , Kumar V. P. S. , Tourigny G. , Delbaere L. T. J.
Published: May 2015

5-methoxymethyl-N4-methyl-2′-deoxycytidine (N4-Me-MMdCyd) and 5-methoxymethyl-N4-methyl-2′-deoxycytidine-5′-monophosphate (N4-Me-MMdCMP) were synthesized to confer resistance to deamination by deaminating enzymes. N4-Me-MMdCyd and N4-Me-MMdCMP were inactive against Herpes simplex virus type 1 (HSV-1) and also nontoxic to VERO cells up to 1796 μM (highest concentration tested). 5-methoxymethyl-2′-deoxycytidine-5′-monophosphate (MMdCMP) was more potent than the nucleoside against HSV-1 in VERO cells. In HSV-infected VERO cells (10 PFU/cell), N4-Me-MMdCyd caused only slight perturbations of deoxyribonucleoside triphosphate pools. 5-methoxymethyl-N4-methyl-2′-deoxycytidine-5′-triphosphate (N4-Me-MMdCTP) was synthesized and the nature of interaction of N4-Me-MMdCTP and dCTP with DNA polymerase of Escherichia coli, HSV-1 and human α was investigated. N4-Me-MMdCTP was neither an effective substrate nor a strong inhibitor of Escherichia coli, HSV-1 or human α DNA polymerase.

The relationship between molecular conformation and antiviral activity for MMdCyd and N4-Me-MMdCyd is discussed. The conformation of the deoxyribofuranose ring in MMdCyd and N4-Me-MMdCyd are different. In N4-Me-MMdCyd, the exocyciic C(5′) side chain has the t conformation whereas MMdCyd has the g+ rotomer conformation. The orientation of the N4-methyl group may also impede binding to the HSV-induced kinase by steric hindrance and/or by hindering hydrogen bonding between the enzyme and the lone pair of electrons at N(3). The results suggest that attempts to render resistance to deamination by alkylation at the N(4) position of the cytosine moiety is not likely to yield compounds with activity against HSV.
Inhibition of Enveloped RNA Virus Formation by Peptides Corresponding to Glycoprotein Sequences
Authors: Collier N. C. , Adams S. P. , Weingarten H. , Schlesinger M. J.
Published: May 2015

Peptides, corresponding to amino acid sequences in the cytoplasmic domains of the transmembranal glycoproteins encoded by Sindbis and vesicular stomatitis viruses, inhibited release of virus particles and infectious virus when added to infected cells for a 2h period during a one-cycle growth curve. Each inhibitory peptide was specific for its intended virus. The shortest peptide with antiviral activity for Sindbis virus contained six amino acids, and a related peptide that was acylated at the amino terminus with octanoic acid was ten-fold more potent as an inhibitor. Neither of these peptides affected the synthesis of viral structural proteins, but a third peptide inhibited proteolytic processing of the Sindbis virus E2 glycoprotein. Inhibition of vesicular stomatitis virus particle release was dose-dependent in the range of 50–400 μg ml−1 for a peptide corresponding to the G glycoprotein cytoplasmic domain. We postulate that these peptides competitively inhibit attachment of the glycoprotein to intracellular virus structures during assembly of the virion. Thus, drugs, based on peptides that mimic the protein-protein interactions required for virus assembly, may have therapeutic potential.
Synthesis and Biological Evaluation of Haloalkyl Phosphate Triester Derivatives of araA and araC
Authors: McGuigan C. , Jones B. C. N. M. , Tollerfield S. M. , Riley P. A.
Published: May 2015

Novel phosphate triester derivatives of the antiviral drug araA and the anti-leukaemic agent araC have been prepared as membrane-soluble pro-drugs of the bio-active free nucleotides. In particular, novel trichloro- and trifluoroethyl phosphates have been prepared using phosphorochloridate chemistry, and are fully characterized. An in vitro assay indicates inhibition, by each of the compounds, of thymidine incor-portion by mammalian epithelial cells. It is notable that the trichloroethyl derivative is most active in each case, and in the case of araC its activity appears to exceed that of the parent nucleoside.
Inhibitory Effect of Pyridobenzoazoles on Orthomyxo-and Paramyxovirus Replication in vitro
Authors: Shigeta S. , Mori S. , Baba M. , Hosoya M. , Mochizuki N. , Chiba T. , De Clercq E.
Published: May 2015

Among thirteen newly synthesized pyridobenzoazole derivatives which have been examined for anti-myxovirus and antiherpesvirus activities, three benzimidazoles emerged as potent anti-orthomyxo- or paramyxovirus compounds. 4-Cyano-2-benzamide-1-oxo-1,5-dihydropyrido[1,2a]benzimidazole (CBO-PB) showed broad antiviral activities against paramyxo-and orthomyxoviruses with EC50 of 0.1–2.0 μg ml−1, and 2-cyano-1-amino derivatives of CBO-PB (CCI-PB) were inhibitory to paramyxoviruses at 1.4–8.5 (μg ml−1 by a plaque reduction method. The third compound, 2-ethoxycarbonyl derivatives of CCI-PB was inhibitory only to respiratory syncytial virus (RSV) at 15–28 μg ml−1. Selectivity indexes of these 3 compounds for RSV in HeLa cells were 60, 86, and >13, respectively. All three compounds inhibited syncytium formation of RSV and Parainfluenzavirus (PFLUV) type 3 at comparable concentrations with EC50 for plaque formation. They inhibited antigen production of RSV and PFLUV at the concentrations that were 4 to 20-fold higher than those needed for plaque reduction, but they did not inhibit adsorption of virus to cells at all. All three compounds inhibited the growth of RSV in HeLa cells at 4-fold higher concentrations than their EC50 for plaque reduction.
Three New Potent HIV-1 Inhibitors from Myxobacteria
Authors: Jurkiewicz E. , Jansen R. , Kunze B. , Trowitzsch-Kienast W. , Forche E. , Reichenbach H. , Höfle G. , Hunsmann G.
Published: May 2015

Three novel compounds, namely, phenoxan, phenalamide A1, and thiangazole, were found to suppress HIV-1 replication in cell cultures. The compounds were discovered by screening crude extracts from myxobacteria and were isolated from two strains of Polyangium sp. and a strain of Myxococcus stipitatus. Their structures have been elucidated. The cytotoxic concentrations for MT-4 cells were 6.6 μM for phenoxan, 102 μM for phenalamide A1, and 4.7 μM for thiangazole. Phenoxan inhibited the HIV-1-dependent cell death at concentrations of as low as 6.6 nM. Phenalamide A1 could prevent the HIV-1 infection of MT-4 cells even at concentrations of 1.02nM, and thiangazole at 4.7 pM. In our assay thiangazole is at least 100 times more active than AZT. The compounds could not prevent syncythia formation induced by HIV-1. However, like HEPT (Baba et al., 1989; Miyasaka et al., 1989) and TIBO (Pauwels et al., 1990) derivatives they are highly specific since they could not interfere with HIV-2ben dependent MT-4 cell death. HIV-1 RT activity was inhibited by 50% by 376 μM phenoxan, 386 μM phenalamid A1, or 263 μM thiangazole. Since these concentrations are approximately 50000 times higher than their minimum concentrations active in cell cultures, RT-inhibition does not appear to be the major mechanism of HIV-inhibition of the new agents.
Poly(Hydroxy)Carboxylates as Selective Inhibitors of Cytomegalovirus and Herpes Simplex Virus Replication
Authors: Neyts J. , Snoeck R. , Wutzler P. , Cushman M. , Klöcking R. , Helbig B. , Wang P. , De Clercq E.
Published: May 2015

Polyhydroxycarboxylates (MW 3800–14000) derived from phenolic (PDP) compounds were found to be selective inhibitors of human cytomegalovirus (CMV), herpes simplex virus type 1 (HSV-1), type 2 (HSV-2), thymidine kinase-deficient (TK−) HSV-1 and vaccinia virus replication at concentrations that are not toxic to the host cells. The PDP compounds were not inhibitory to parainfluenza virus, reovirus, Sindbis virus, or Semliki forest virus. The polycarboxylate aurintricarboxylic acid (ATA) (MW 1149–3336) also proved inhibitory to CMV and HSV replication. The anti-CMV and anti-HSV activities of the ATA polymers increased with increasing molecular weight. The mechanism of anti-CMV activity of both the PDP and ATA series of compounds can be attributed to the inhibition of virion attachment to the cells, probably due to an interaction of these polyanionic compounds with the positively charged domains of the viral envelope glycoproteins.
In vitro Toxicity of 2′,3′-Dideoxy-3′-Thiacytidine (BCH189/3TC), a New Synthetic Anti-HIV-1 Nucleoside
Authors: Lisignoli G. , Facchini A. , Cattini L. , Monaco M. C. G. , Degrassi A. , Mariani E.
Published: May 2015

2′,3′-Dideoxy-3′-thiacytidine (BCH189 or 3TC, IAF BioChem International Inc., Montreal, Canada) is a new synthetic anti-HIV-1 dideoxynucleoside with a sulphur atom in the heterocycle ring. Preclinical studies showed that this compound at 5–10 μM displays potent anti-retroviral activity in vitro against HIV-1 infected T (H9 and MT4) and monocyte/macrophage (U937) cell lines, associated with low acute and chronic myelotoxicity in animals.

The present study evaluates the in vitro toxicity of BCH189 in comparison with 3′-azido-2′,3′-dideoxythymidine (AZT) on peripheral blood lymphocytes (PBL) from normal subjects and asymptomatic HIV-1 seropositive patients. BCH189 and AZT were used at concentrations ranging from 0.01 to 50 μM, and their action was analysed by: (1) proliferation assay using two activation pathways (concanavalin A and anti-CD3 monoclonal antibody), (2) natural killer (NK) activity, and (3) IL2 receptor (CD25) expression after stimulation with concanavalin A (ConA). Exposure of PBL for 72 h to the two drugs resulted in decreased DNA synthesis only in cells treated with AZT. In particular, BCH189 did not modify significantly cellular proliferation, while a significant inhibition of PBL from normal subjects and HIV-1 positive patients, was observed at AZT concentrations ranging between 5 to 50 μM. Both 2′,3′-dideoxy-3′-thiacytidine (BCH189) and AZT had no effect on NK cytolytic activity.

BCH189, at various doses, did not interfere with IL2 receptor (CD25) expression on CD3 positive cells, while AZT, only at very high concentration (50μM), caused a decrease in the number of CD25 positive cells. These studies suggest that BCH189 is less toxic in vitro to lymphocytes than AZT and further support its use in clinical trials on HIV-1 infected subjects as a good alternative to AZT.
Antiviral Effect of Interferon Therapy for Patients with Chronic Hepatitis C
Authors: Hayashi J. , Nakashima K. , Noguchi A. , Hirata M. , Akazawa K. , Kashiwagi S.
Published: May 2015

Thirty-two patients with chronic hepatitis who were positive for hepatitis C virus (HCV) RNA by polymerase chain reaction and had antibody to HCV (anti-HCV), were enrolled in this study. Twenty of them were also positive for antibody to the GOR epitope (anti-GOR). Sixteen of the enrolled patients were treated with human lymphoblastoid interferon for six months. Treatment was initiated with 3 million units of interferon daily for 2 weeks, followed by 3 million units three times a week for 6 weeks and 1.5 million units three times a week for 16 weeks. The efficacy of therapy was assessed by comparison with the results in 16 untreated patients. Aminotransferase values, titre of anti-HCV and anti-GOR antibodies showed significant decreases throughout the therapy compared with baseline levels and the untreated patients. After a 3 month follow-up, nine treated patients (56.3%) had normal aminotransferase activities and six of them eliminated HCV RNA from their sera (37.5%). Three of these six patients became negative for both anti-HCV and anti-GOR antibodies (18.8%). None of the untreated control patients had normal aminotransferase activities or became negative for HCV markers. The present study suggests that human lymphoblastoid interferon can control the disease activity and eliminate hepatitis C virus from patients with chronic hepatitis C.
New Polyacetal Polysulphate Active against Human Immunodeficiency Virus and other Enveloped Viruses
Authors: Witvrouw M. , Schols D. , Andrei G. , Snoeck R. , Ikeda S. , Pauwels R. , Van Schepdael A. , Arnout J. , Claes P. , Desmyter J. , De Clercq E.
Published: May 2015

A new polyacetal polysulphate, termed PAPS, was synthesized starting from dextran through oxidation, reduction, and subsequent sulphation. PAPS inhibited HIV-1- and HIV-2-induced cytopathicity in MT-4 cells at concentrations comparable to those required for dextran sulphate (MW5000) to inhibit the cytopathicity of these viruses (50% inhibitory concentration: 0.4–0.04 μg ml−1). At these concentrations PAPS had no anticoagulant activity. PAPS suppressed syncytium formation between MOLT-4 cells and persistently HIV-1- or HIV-2-infected HUT-78 cells at a concentration of 1 μg ml−1, that is 25- to 30-fold lower than that required for dextran sulphate to inhibit syncytium formation. Like dextran sulphate, PAPS inhibited HIV-1 binding to the cells and anti-gp120 mAb binding to HIV-1 gp120. Also, PAPS proved equally active as dextran sulphate against herpes simplex virus, cytomegalovirus and the arenaviruses Junin and Tacaribe, and 10-fold more active than dextran sulphate against vaccinia, Sindbis, influenza A, and vesicular stomatitis virus. Neither PAPS nor dextran sulphate proved inhibitory to the non-enveloped viruses polio, Coxsackie and reovirus. Pharmacokinetic studies in rabbits revealed that after intravenous bolus injection the serum concentrations of PAPS decayed biphasically, with an initial half-life of approximately 45–60 min. Twenty-four hours following their intraperitoneal administration to mice, PAPS as well as dextran sulphate generated low titres of an antiviral principle that was at least partially interferon-like.
In vitro Antiviral Activity of Ribavirin against Picornaviruses
Authors: Andersen D. O. , Murray B. K. , Robins R. K. , North J. A.
Published: May 2015

The in vitro antiviral activity of ribavirin (Rby; 1-β-D-ribof uranosyl-1,2,4-triazole-3-carboxamide) against selected members of the Picornaviridae is described. When antiviral activity was determined by reduction of infectious virus progeny, Rbv was active against human rhinovirus type 2 (HRV-2) and poliovirus type 1 (Polio-1) in both a drug concentration and multiplicity of infection-(MOI) dependent response. However, an antiviral activity rating assay based on the reductions of cellular cytopathic effects (CPE) indicated that Rbv was active against human rhinoviruses, but was less active against polioviruses. Prophylactic administration of Rbv significantly improved virus yield reduction, especially in Polio-1. SDS Polyacrylamide gel electrophoresis (SDS-PAGE) of HRV-2- and Polio-1-infected cell lysates demonstrated that Rbv inhibited the synthesis of viral-specific proteins. Although actinomycin D (Act D) did not significantly influence Picornavirus yields, when added concomitantly with Rbv, Act D reversed Rbv's antiviral effect.
Antipicornavirus Compounds: Use of Rational Drug Design and Molecular Modelling
Authors: Diana G. D. , Nitz T. J. , Mallamo J. P. , Treasurywala A.
Published: May 2015

The discovery of antipicornavirus activity associated with disoxaril 1 and related compounds, and the elucidation of the 3-dimensional structure of human rhinovirus-14 and −1A has lead to the use of rational drug design in the search for more potent and broad spectrum agents. The use of volume maps based on the X-ray conformation of these compounds in human rhinovirus-14 has revealed space filling requirements for activity for this serotype which has been confirmed by the use of the programme CoMFA. The principle interactions of the compounds within the binding site appear hydrophobic in nature. These studies have shown that maximum occupancy of the binding site is associated with good antiviral activity.
Synthesis and Anti-HIV Activity of Prodrugs of Azidothymidine
Authors: Sharma A. P. , Ollapally A. P. , Lee H. J.
Published: May 2015

In order to enhance the therapeutic efficacy of azidothymidine (AZT) by improving its pharmacokinetic properties, three prodrugs of AZT were synthesized by esterifying the 5′-hydroxyl of AZT with three pharmacologically inactive steroidal 17β-carboxylic acids. Preliminary results of in vitro anti-HIV activity screening of the compounds show that all of these esters have anti-HIV activity comparable to that of AZT. This report discusses the synthesis and anti-HIV activity screening results of the prodrugs.
Synergistic Antiviral Activity of Inhibitors of S-Adenosylhomocysteine Hydrolase and Ribavirin
Authors: Ishii H. , Hasobe M. , McKee J. G. , Ault-Riché D. B. , Borchardt R. T.
Published: May 2015

(1′R,2′S,3′R)-9-(2′,3′-Dihydroxycycloperrt-4′-en-1′-yl)-adenine (DHCeA) and -3-deazaadenine (3-deaza-DHCeA), which are potent inhibitors of S-adenosylho-mocysteine (AdoHcy) hydrolase, and ribavirin, which is an inhibitor of IMP-dehydrogenase, were found in this study to have synergistic effects on inhibiting vaccinia virus replication in murine L929 cells without creating a synergistic effect on cellular toxicity. Thus, the antiviral effectiveness of this drug combination was 5–10× higher than the antiviral effectiveness observed with the AdoHcy hydrolase inhibitors alone. Ribavirin does not alter the ability of DHCeA and 3-deaza-DHCeA to elevate the intracellular AdoHcy/S-adeno-sylmethionine (AdoMet) ratio. Increases in this ratio were shown earlier to correlate with the antiviral effects of these carbocyclic nucleosides. Ribavirin was also shown to significantly reduce the cellular level of GTP, which is consistent with its activity as an inhibitor of IMP-dehydrogenase and its proposed mechanism of antiviral action, inhibiting the formation of the ‘capped methylated structure’ at the 5′-end of viral mRNA.
Intermittent Zidovudine Regimen in Patients with Symptomatic HIV Infection and Previous Haematological Toxicity
Authors: Williams I. G. , Tedder R. S. , Weller I. V. D.
Published: May 2015

Thirteen patients with AIDS or ARC on continuous zidovudine therapy (800–1200 mg daily), who developed severe anaemia (median Hb 7.9g dl−1 range 4.9–9.4) after 66 days of treatment (median, range 35–258) were then treated with an intermittent regimen in an open study. The regimen consisted of cycles of 4 weeks on treatment (600–100 mg daily) followed by 2 weeks off. Intermittent treatment was tolerated for a significantly longer period of time (median 257 days range 72–603) and a higher cumulative does ( P < 0.001). Four patients discontinued intermittent therapy in the period of follow-up, three due to bone marrow suppression. Eight of 13 patients needed red cell transfusions on continuous therapy compared to only one on the intermittent regimen. On intermittent therapy median haemoglobin concentration and neutrophil counts remained stable (Hb median 11.9g dl−1 range 9.1–14.8, neut. median 1.7 × 109I−1 range 0.6–4.3). Ten patients had detectable levels of P24 antigen which decreased from a median of 128 pg ml−1 (range 15–242) to 24 pg ml−1 (range 0–53) on continuous therapy. Subsequently, in eight of these patients on the intermittent regimen, levels of P24 Ag remained below 50% of initial pretreatment values (median 28 pg ml−1 range 0–178) or below 50 pg ml−1.
Antiviral Synergy between Inhibitors of HIV Proteinase and Reverse Transcriptase
Authors: Craig J. C. , Duncan I. B. , Whittaker L. , Roberts N. A.
Published: May 2015

Ro 31–8959, a potent and specific inhibitor of HIV proteinases, is shown to interact synergistically in combination with nucleoside analogue inhibitors of HIV reverse transcriptase (AZT, ddC, 2′-FddC). Ninety per cent inhibition endpoints (IC90), obtained from checkerboard titrations of compound mixtures on CEM-T4 cells infected with HIV-i strain GB8, have been further analysed. Compared with concentrations needed when inhibitors are used individually, reductions of between 2- and 30-fold were observed in combination, depending on the nucleoside analogue and the ratio of concentrations employed. The results suggest that combinations of AZT or ddC with Ro 31–8959 should be considered for development as candidate antiviral treatments of patients with HIV infection.
Antiherpes Effect of Dextran Sulphate Combined with Acyclovir in vitro and in vivo
Authors: Pancheva S. N.
Published: May 2015

The combined antiviral effect of dextran sulphate (DS, MW 40000) and acyclovir (ACV) on herpes simplex virus type 1 (HSV-1) and Pseudorabies virus (PRV) in vitro and on experimental HSV-1 keratitis in rabbits, was studied. Dextran sulphate in combination with ACV results in synergistic effect, as measured by yield reduction assay and on herpes simplex keratitis in rabbits. The better therapeutic effect of the combination was proved by the decreased severity of ocular infection and the reduction of the virus shedding in tear film.
Establishment of the Haemadsorption-Based Colorimetric Assay for the Screening of Anti-Influenza Compounds
Authors: Takeuchi H. , Baba M. , Shigeta S.
Published: May 2015

We established a haemadsorption-based colorimetric assay system, which may be used to screen a large number of anti-influenza compounds. Madin Darby canine kidney (MDCK) cells infected with influenza virus were cultured in the presence of test compounds and after 3 days of infection guinea pig erythrocytes (GPE) were added to infected MDCK cells. After 4 washings of the cells the adsorbed GPE were lysed with distilled water, and peroxidase activities contained in GPE were measured using o-phenylendia-mine and H2O2 as substrates. The peroxidase activity that was read as optical density of oxidized o-phenylendiamine (quinoid form) correlated well with the dose of virus and day of infection in MDCK cells. Fifty per cent inhibitory concentration (IC50) of 1-(β-D-ribofuranosyl)-1,2,4-triazole-3-carboxamide (ribavirin) and adamantanamine hydrochloride (amantadine) against influenza virus A/H3N2/lshikawa and influenza B/Singapore, the IC50s of ribavirin to influenza A and B were 0.5 μg ml−1 to 1.0 μg ml−1 respectively. On the other hand, the IC50 of amantadine for influenza A was 1 μg ml−1 but was more than 100 μg ml−1 for influenza B virus. By this method, ribavirin, 5-ethynyl-1-β-D-ribofuranosylimidazole-4-carboxamide (EICAR), 3-(β-D-ribofuranosyl)-4-hydroxypyrazole-5-carboxamide (pyrazofurin) have shown inhibitory effects for virus replication at lower concentrations than their cytotoxic doses. On the other hand carbocyclic citidine (carbodine) was cytotoxic at the concentration of virus inhibition. Ribavirin and pyrazofurin showed one tenth or less EC50 for influenza A and B viruses by the haemadsorption-based colorimetric assay compared with the ECso by TCID50 method. It is possible to estimate the inhibitory effect of antiviral compounds against influenza viruses rapidly and quantitatively by this colorimetric assay system.
Rapid Prescreening for Antiviral Agents against HIV-1 Based on Their Inhibitory Activity in Site-Directed Immunoassays. Approaches Applicable to Epidemic HIV-1 Strains
Authors: Neurath A. R. , Strick N. , Jiang S.
Published: May 2015

Several compounds, including the triphenylmethane derivative aurintricarboxylic acid (ATA) and porphyrins, were reported to inhibit the binding of anti-V3 loop-specific antibodies to the V3 loop of gp120 from HIV-1 III-B and to have antiviral activity, probably due to interference with the biological function of the V3 loop. However, these compounds can be applied to antiviral chemotherapy only if they interact with envelope glycoproteins from a multitude of epidemic HIV-1 strains and inhibit their replication. Since recombinant envelope glycoproteins, synthetic peptides and anti-V3 monoclonal antibodies may not be available for these HIV-1 strains, alternative assays are needed to prescreen different compounds for potential antiviral activity against these viruses. Results presented here indicate that: (1) virions of HIV-1 MN, most closely related to primary HIV-1 isolates from European and North American countries, and human anti-HIV-1 antibodies, can also be used for rapid prescreening of antiviral agents, (2) compounds with antiviral activity against HIV-1 MN, discerned by site-directed immunoassays, inhibited the reaction of human anti-HIV-1 with a V3 loop consensus peptide corresponding to European/North American HIV-1 isolates, and (3) meso-tetra (4-carboxyphenyl) porphine (MTCPP), one of the most potent inhibitors of HIV-1 replication selected on the basis of site-directed immunoassays, preferentially attached to the V3 loop of gp120.