Check out our New Publishers' Select for Free Articles

Antiviral Research (v.72, #1)

Editorial Board (pp. ii).

Notes to Authors (pp. co3).

Guide for Authors (pp. v-xi).

Antiviral effects of glycosylation and glucose trimming inhibitors on human parainfluenza virus type 3 by Yoshikazu Tanaka; Junko Kato; Michinori Kohara; Mark S. Galinski (pp. 1-9).

Endoplasmic reticulum (ER) α-glucosidase inhibitors block the trimming of N-linked glycosylation and thus prevent the production of several viruses. The present study investigates the antiviral effects of the α-glucosidase and α-mannosidase inhibitors (castanospermine, 1-deoxynojirimycin, bromoconduritol, deoxymannojirimycin and swainsonine) on human parainfluenza virus type 3 (HPIV3). The α-glucosidase inhibitors (castanospermine, 1-deoxynojirimycin) in recombinant expression systems reduced the surface and intracellular expression of both HPIV3 F and HN proteins. On the other hand, α-mannosidase inhibitors prevented processing of the oligosaccharides on HPIV3 glycoproteins into the complex form. Consequently, α-glycosidase inhibitors (castanospermine and 1-deoxynojirimycin) significantly inhibited viral fusion activity. We demonstrated that the α-glucosidase inhibitors (castanospermine and 1-deoxynojirimycin) reduced the infectivity of newly released viral particles. We postulate that α-glucosidase inhibitors can prevent the first steps of HPIV3 envelope glycoprotein processing and that the inhibition of glucose trimming has antiviral effects.

Keywords: Human parainfluenza virus type 3; Oligosaccharide processing; Glycosylation inhibitors

Synthesis and antiviral evaluation of alkoxyalkyl esters of acyclic purine and pyrimidine nucleoside phosphonates against HIV-1 in vitro by Nadejda Valiaeva; James R. Beadle; Kathy A. Aldern; Julissa Trahan; Karl Y. Hostetler (pp. 10-19).

Alkoxyalkyl esters of cidofovir, an acyclic nucleoside phosphonate, have been shown to have antiviral activities several orders of magnitude greater than unmodified cidofovir against cytomegalovirus, herpes simplex virus, vaccinia, cowpox, ectromelia and adenoviruses in vitro. Hexadecyloxypropyl-cidofovir is orally bioavailable and active in lethal animal models of vaccinia, cowpox, ectromelia and cytomegalovirus. To see if this strategy is also applicable to other acyclic nucleoside phosphonates, we have converted several phosophonomethoxyethyl purines and pyrimidines to their hexadecyloxypropyl, octadecyloxyethyl and oleyloxyethyl esters and compared their activity against HIV-1 with the activity of the respective unmodified acyclic nucleoside phosphonates. The hexadecyloxypropyl esters of phosphonomethoxyethyl-adenine, phosphonomethoxyethyl-2,6-diaminopurine and phosphonomethoxyethyl- N⁶-cyclopropyl-diaminopurine were 3–5 orders of magnitude more active against HIV-1 in vitro than the parent nucleotides. The EC₅₀ values for these compounds were in the 10–20pM range with selective indexes of 1250 to >4000. The acyclic pyrimidine phosphonates were generally inactive against HIV-1 in vitro. Phosphonomethoxyethyl-cytosine and phosphonomethoxyethyl-5-fluorocytosine were inactive against HIV-1. Surprisingly, hexadecyloxypropyl-phosphonomethoxyethyl-5-fluorocytosine was active against HIV-1 with a submicromolar EC₅₀ and a selective index of 174. Esterification of acyclic nucleoside phosphonates with alkoxyalkyl moieties may represent a general approach for increasing antiviral activity and selectivity of this class of antivirals.

Keywords: HIV; Acyclic nucleoside phosphonates; Prodrugs; Alkoxyalkyl esters

Inhibition of feline (FIPV) and human (SARS) coronavirus by semisynthetic derivatives of glycopeptide antibiotics by Jan Balzarini; Els Keyaerts; Leen Vijgen; Herman Egberink; Erik De Clercq; Marc Van Ranst; Svetlana S. Printsevskaya; Eugenia N. Olsufyeva; Svetlana E. Solovieva; Maria N. Preobrazhenskaya (pp. 20-33).

Various semisynthetic derivatives of glycopeptide antibiotics including vancomycin, eremomycin, teicoplanin, ristocetin A and DA-40926 have been evaluated for their inhibitory activity against feline infectious peritonitis virus (FIPV) and human (SARS-CoV, Frankfurt-1 strain) coronavirus in cell culture in comparison with their activity against human immunodeficiency virus (HIV). Several glycopeptide derivatives modified with hydrophobic substituents showed selective antiviral activity. For the most active compounds, the 50% effective concentrations (EC₅₀) were in the lower micromolar range. In general, removal of the carbohydrate parts of the molecules did not affect the antiviral activity of the compounds. Some compounds showed inhibitory activity against both, whereas other compounds proved inhibitory to either, FIPV or SARS-CoV. There was no close correlation between the EC₅₀ values of the glycopeptide derivatives for FIPV or SARS-CoV.

Keywords: Coronaviruses; FIPV; SARS; Glycopeptide antibiotics; Vancomycin; Teicoplanin; Eremomycin

A rapid quantitative PCR-based assay for testing antiviral agents against human adenoviruses demonstrates type specific differences in ribavirin activity by Rüdiger Stock; Gabi Harste; Ijad Madisch; Albert Heim (pp. 34-41).

Human adenovirus (HAdV) infections are increasingly frequent and potentially fatal as a disseminated disease in highly immunocompromised patients. Determining the in vitro sensitivity of HAdV to antiviral agents is not an easy task because HAdV CPE reduction assays are difficult to interpret and may take more than 1 week. We developed a phenotypic assay for testing the antiviral activity during the first round of replication using HAdV DNA concentration as an objective readout within 30h. After evaluating the assay with cidofovir, we focused on determining the antiviral of ribavirin against different HAdV serotypes because clinical response of HAdV infections towards ribavirin treatment varied considerably.Several HAdV prototypes (1, 2, 5, 11, 31, 34, 48) associated with disseminated infections and clinical isolates were tested. Predominating HAdV of species C were more sensitive to ribavirin (HAdV-2 and -5: EC₅₀<10μM, EC₉₉ 111 and 104μM, respectively) than HAdV of other species, for example HAdV-31 (EC₅₀ 56μM, EC₉₉>500μM). Differential ribavirin sensitivity of HAdV types may contribute to the variable outcome of ribavirin therapy. Rapid screening of antiviral agents with the rapid qPCR-based assay against a multitude of HAdV serotypes may also facilitate development of future antiviral agents.

Keywords: Adenovirus; Ribavirin; Phenotypic assay; Quantitative PCR; Immunosuppression

Protection of Balb/c mice against infection with FMDV by immunostimulation with CpG oligonucleotides by Søren Kamstrup; Tine Holland Frimann; Annette Malene Barfoed (pp. 42-48).

Oligodeoxynucleotides (ODN) containing unmethylated CpG motifs are potent stimulators of the innate immune system, and are capable of aborting several infections in a non-specific manner. We here report studies of the capacity of such ODN to protect mice against infection with foot and mouth disease virus (FMDV). Susceptibility of Balb/c mice to infection with isolates from the different serotypes of FMDV was investigated, and, at the same time, the capacity of CpG ODN to modulate the infection was evaluated. Treatment with CpG significantly reduced viremia, disease and death in five of six serotypes, when compared to no treatment or treatment with a control ODN. The effect was observed when ODN was administered simultaneously with, or up to 12h after, infection with FMDV, and lasted for 14 days post treatment. The potential application of CpG ODN for control of FMDV during an outbreak is discussed.

Keywords: Foot and mouth disease virus; CpG ODN; Protection

Identification of inhibitors to papillomavirus type 16 E6 protein based on three-dimensional structures of interacting proteins by James D. Baleja; Jonathan J. Cherry; Zhiguo Liu; Hua Gao; Marc C. Nicklaus; Johannes H. Voigt; Jason J. Chen; Elliot J. Androphy (pp. 49-59).

Human papillomaviruses (HPV) cause cutaneous and genital warts. A subset of HPV types is associated with a high-risk for progression to malignancy. The E6 protein from the high-risk HPV types represents an attractive target for intervention because of its roles in viral propagation and cellular transformation. E6 functions in part by interaction with human cellular proteins, several of which possess a helical E6-binding motif. The role for each amino acid in this motif for binding E6 has been tested through structure determination and site-directed mutagenesis. These structural and molecular biological approaches defined the spatial geometry of functional groups necessary for binding to E6. This E6-binding information (the E6-binding pharmacophore) was transferred into a three-dimensional query format suitable for computational screening of large chemical databases. Compounds were identified and tested using in vitro and cell culture-based assays. Several compounds selectively inhibited E6 interaction with the E6-binding protein E6AP and interfered with the ability of E6 to promote p53 degradation. Such compounds provide leads for the development of new pharmacologic agents to treat papillomavirus infections and their associated cancers.

Keywords: Papillomavirus; HPV-16; E6; In silico screening; Antiviral; Protein–protein interaction

Antiviral properties of new arylsulfone derivatives with activity against human betaherpesviruses by Lieve Naesens; Chad E. Stephens; Graciela Andrei; Arianna Loregian; Leen De Bolle; Robert Snoeck; J. Walter Sowell; Erik De Clercq (pp. 60-67).

Based on our previous experience with arylsulfone derivatives displaying antiherpetic activity, we synthesized several analogues in which the sulfonyl group is part of a bicyclic structure . The benzene-fused derivative 2 H-3-(4-chlorophenyl)-3,4-dihydro-1,4-benzo-thiazine-2-carbonitrile 1,1-dioxide and its thiophene-fused analogue were shown to have favorable activity and selectivity against the betaherpesviruses human cytomegalovirus (HCMV) and human herpesvirus 6 (HHV-6) and 7 (HHV-7). The benzene-fused derivative retained its anti-HCMV activity when evaluated against virus strains resistant to foscarnet, ganciclovir, and/or cidofovir. The compound conferred ≥95% inhibition of viral DNA synthesis in HHV-6-infected cells. RT-PCR analysis of immediate-early, early and late gene products revealed that this arylsulfone compound acts at a step preceding late gene expression, and coinciding with the inhibition exerted by foscarnet. No inhibitory effect was seen in an enzyme assay for DNA elongation catalyzed by the HCMV or HHV-6 DNA polymerase catalytic subunit. The arylsulfone derivatives had no effect on the functional interaction between the catalytic subunit of HCMV DNA polymerase and its accessory protein, nor did they disrupt the physical interaction between the two proteins. We conclude that these arylsulfone derivatives represent new betaherpesvirus inhibitors with a novel mode of action that results in indirect inhibition of viral DNA synthesis.

Keywords: Cytomegalovirus; Human herpesvirus 6; Betaherpesvirus; Antiviral; Arylsulfone derivative

Experimental study on the action of allitridin against human cytomegalovirus in vitro: Inhibitory effects on immediate-early genes by Hong Zhen; Feng Fang; Du-yun Ye; Sai-nan Shu; Yu-feng Zhou; Yong-sui Dong; Xing-cao Nie; Ge Li (pp. 68-74).

Garlic ( Allium sativum) extraction has been reported having anti-HCMV efficacy. This study was aimed to investigate the effect of allitridin (diallyl trisulfide, a compound from A. sativum extraction) on the replication of HCMV and the expression of viral immediate-early genes. In HCMV plaque-reduction assay, allitridin appeared a dose-dependent inhibitory ability with EC₅₀ value of 4.2μg/ml (selective index, SI=16.7). Time-of-addition and time-of-removal studies showed that allitridin inhibited HCMV replication in earlier period of viral cycle before viral DNA synthesis. Both immediate early gene (ie1) transcription and IEA (IE₁72 and IE₂86) expression was suppressed by allitridin, but not by GCV in a single HCMV cycle format. In addition, allitridin appeared stronger inhibition on IE₂86 than on IE₁72. Decrease of viral DNA load in infected cells was also detected under allitridin treatment, probably due to an indirect consequence of the reduction in ie gene transcription. In summary, this study indicated that allitridin has anti-HCMV activity and the mechanism is associated with suppression of ie gene transcription.

Keywords: Cytomegalovirus; Allium sativum; Diallyl trisulfide; Cytomegalovirus; Immediate-early gene

Sections

Personal tools

Antiviral Research (v.72, #1)

Sections

Personal tools

Local resources

Antiviral Research (v.72, #1)