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Antiviral Research (v.71, #1)
Distinct thymidine kinases encoded by cowpox virus and herpes simplex virus contribute significantly to the differential antiviral activity of nucleoside analogs by Mark N. Prichard; Angela D. Williams; Kathy A. Keith; Emma A. Harden; Earl R. Kern (pp. 1-6).
Orthopoxviruses and herpesviruses are both large enveloped DNA viruses, yet these virus families exhibit very different susceptibilities to antiviral drugs. We investigated the activation of nucleoside analogs by the types I and II thymidine kinase (TK) homologs expressed by herpes simplex virus type 1 (HSV-1) and cowpox virus (CV). Antiviral activity against TK− and TK+ strains of HSV-1 and CV was determined, and the ratio of the EC50 values was used as a measurement of TK dependence. As to HSV-1, most of the selected compounds were markedly less effective against the TK− strains, suggesting that this enzyme was required for the activation of these nucleoside analogs. This differs from the results for CV where only idoxuridine and bromodeoxyuridine appeared to be activated, putatively by the type II TK expressed by this virus. These data confirm that the type II TK encoded by CV exhibits a more limited substrate specificity than the type I TK encoded by HSV-1. These data suggest that the inefficient activation of nucleoside analogs by the orthopoxvirus TK significantly limits their activity. Additional screening against orthopoxviruses will be required to identify nucleoside analogs that are efficiently activated by their type II TK.
Keywords: Orthopoxviruses; Herpesviruses; Thymidine
Synthesis and the biological evaluation of 2-benzenesulfonylalkyl-5-substituted-sulfanyl-[1,3,4]-oxadiazoles as potential anti-hepatitis B virus agents by Theresa May Chin Tan; Yu Chen; Kah Hoe Kong; Jing Bai; Yang Li; Seng Gee Lim; Thiam Hong Ang; Yulin Lam (pp. 7-14).
Current treatments for chronic hepatitis B virus (HBV) infection include the use of interferon-α and of nucleoside analogs lamivudine, adefovir and entecavir. However, the use of interferon-α has many side effects while that of nucleosidic inhibitors can lead to the emergence of resistant viruses. Hence, new drugs for the treatment of HBV infection are still highly desired. Oxadiazoles have been observed to exhibit antiviral activities against RNA viruses. In this study, a facile synthesis of 2-benzenesulfonylalkyl-5-substituted-sulfanyl-[1,3,4]-oxadiazoles is reported. The compounds were then evaluated for their anti-HBV activity. 1-{2-[5-(1-Benzenesulfonyl-propyl)-[1,3,4]oxadiazol-2-yl-sulfanyl]-ethyl}-4-(2-methoxy-phenyl)-piperazine (1i) was able to inhibit the expression of the viral antigens, HBsAg and HBeAg in a concentration-dependent manner with no cytotoxic effects and without any effects on the expression of viral transcripts. Concentration- and time-dependent reductions in virion production were also observed. The inhibition of virion production was comparable to that of lamivudine and EC50 values of 1.63 and 2.96μM were obtained for compound1i and lamivudine, respectively. Thus, in addition to the antiviral effects on RNA viruses, oxadiazoles also have anti-HBV activities.
Keywords: Hepatitis B virus; Hepatitis B virus-s antigen; Hepatitis B virus-e antigen; Antiviral activity; Oxadiazoles
Discovery of TSAO derivatives with an unusual HIV-1 activity/resistance profile by Sonia de Castro; Carlos García-Aparicio; Kristel Van Laethem; Federico Gago; Esther Lobatón; Erik De Clercq; Jan Balzarini; María-José Camarasa; Sonsoles Velázquez (pp. 15-23).
The very first TSAO derivative that lacks the 4″-amino group at the 3′-spiro moiety (compound3) has been prepared and the effect of this modification on the activity/resistance profile has been evaluated. This molecule proved HIV-1 specific (NNRTI-characteristic). A mixture of wild-type and V106V/A or L234L/I mutations were found in the RT of some, but not all compound3-resistant virus strains. Compound3 does not select for the TSAO-specific E138K mutation in the RT. However, the compound markedly lost its antiviral potential against a variety of virus strains that contain NNRTI-characteristic mutations in RT including E138K. The deaminated TSAO compound must fit differently in the HIV-1 RT enzyme than its prototype TSAO-m3T.
Keywords: Abbreviations; TSAO; [2′,5′-bis-; O; -(; tert; -butyldimethylsilyl)-β-; d; -ribofuranosyl]-3′-spiro-5″-(4″-amino-1″,2″-oxathiole-2″,2″-dioxide) nucleosideDeaminated TSAO; TSAO compounds; Non-nucleoside HIV-1 RT inhibitors; Spironucleosides
In vitro and in vivo evaluation of isatin-β-thiosemicarbazone and marboran against vaccinia and cowpox virus infections by Debra C. Quenelle; Kathy A. Keith; Earl R. Kern (pp. 24-30).
It has been reported previously that some thiosemicarbazone compounds have prophylactic activity against smallpox disease and therapeutic activity against vaccinia virus (VV) infections. In these studies, isatin-β-thiosemicarbazone (IBT) and marboran were administered once daily by intraperitoneal (ip) injection to mice using 30, 10 or 3mg/kg for 5 days beginning 24, 48 or 72h after inoculation with VV or cowpox virus (CV). Both compounds were highly effective ( p<0.01) at preventing mortality due to VV even when treatment was delayed up to 72h postinfection. In CV-infected mice, neither IBT nor Marboran were effective in preventing mortality at any dosage tested when administered at 24h postinoculation. Viral replication in liver, spleen and kidney was delayed or reduced by 100–to 10,000-fold by 10mg/kg of marboran, but not IBT, in VV infections. Neither compound was effective against CV infection. Neither IBT nor marboran treatment of mice cutaneously infected with VV or CV reduced viral replication or clinical disease. These results suggest that this class of compound has little therapeutic potential for orthopoxvirus infections since the in vivo activity against CV, a surrogate virus for variola, is lacking.
Keywords: Orthopoxvirus; Antiviral; Animal model; IBT; Marboran
Inhibition of respiratory syncytial virus in cultured cells by nucleocapsid gene targeted deoxyribozyme (DNAzyme) by Yuan-Yuan Xie; Xiao-Dong Zhao; Li-Ping Jiang; Hong-Li Liu; Li-Jia Wang; Ping Fang; Kun-Ling Shen; Zheng-De Xie; Ya-Ping Wu; Xi-Qiang Yang (pp. 31-41).
Respiratory syncytial virus (RSV), which presents the primary cause of bronchiolitis and pneumonia among infants and causes significant morbidity and mortality in immunodeficient patients, remains a health problem worldwide. Unfortunately, an effective vaccine is currently unavailable and pharmacologic treatment needs further optimization for RSV disease. Because RSV is a non-segmented negative-strand RNA virus, it may be sensitive to the genome RNA cleaving by DNAzyme, an artificial nucleic acids molecule with high catalytic capability of cleaving complementary RNA molecules. Thus, RSV-targeted DNAzymes potentially present as a therapeutic candidate of RSV diseases. In this study, DNAzymes targeting the RSV genomic RNA or mRNA were designed and synthesized, one of which (DZn1133) did cleave RSV RNA in vitro, inhibit the transcription and expression of F viral gene, reduce the RSV yield by about 7 logs and protect more than 90% RSV-infected Hep-2 cells from a cytopathic effect at 8μM. Moreover, 10 wild RSV strains isolated from clinic patients including both subgroups A and B were all suppressed by DZn1133 with greater anti-RSV activity than antisense DNA or ribavirin.
Keywords: Deoxyribozyme (DNAzyme); Respiratory syncytial virus; Antiviral; Nucleocapsid
Increasing prevalence of HIV-1 protease inhibitor-associated mutations correlates with long-term non-suppressive protease inhibitor treatment by R.M. Kagan; P.K. Cheung; T.K. Huard; M.A. Lewinski (pp. 42-52).
Treatment of human immunodeficiency virus type 1 with protease inhibitors (PIs) is associated with the emergence of resistance-associated mutations. Treatment-characterized datasets have been used to identify novel treatment-associated protease mutations. In this study, we utilized two large reference laboratory databases (>115000 viral sequences) to identify non-established resistance-associated protease mutations. We found 20 non-established protease mutations occurring in 82% of viruses with a PI resistance score of 4–7, 62% of viruses with a resistance score of 1–3, and 35% of viruses with no predicted PI resistance. We correlated mutational prevalence to treatment duration in a treatment-characterized dataset of 2161 patients undergoing non-suppressive PI therapy. In the non-suppressed dataset, 24 mutations became more prevalent and three mutations became less prevalent after more than 48 months of non-suppressive PI-therapy. Longer durations of non-suppressive treatment correlated with higher PI resistance scores. Mutations at eight non-established positions that were more common in viruses with the longest duration of non-suppressive therapy were also more common in viruses with the highest PI resistance score. Covariation analysis of 3036 protease amino acid substitutions identified 75 positive and nine negative correlations between resistance associated positions. Our findings support the utility of reference laboratory datasets for surveillance of mutation prevalence and covariation.
Keywords: HIV-1; Protease resistance mutations; Protease inhibitors; Treatment duration; Covariation; Comutation
Enhancement of the infectivity of SARS-CoV in BALB/c mice by IMP dehydrogenase inhibitors, including ribavirin by Dale L. Barnard; Craig W. Day; Kevin Bailey; Matthew Heiner; Robert Montgomery; Larry Lauridsen; Scott Winslow; Justin Hoopes; Joseph K.-K. Li; Jongdae Lee; Dennis A. Carson; Howard B. Cottam; Robert W. Sidwell (pp. 53-63).
Because of the conflicting data concerning the SARS-CoV inhibitory efficacy of ribavirin, an inosine monophosphate (IMP) dehydrogenase inhibitor, studies were done to evaluate the efficacy of ribavirin and other IMP dehydrogenase inhibitors (5-ethynyl-1-β-d-ribofuranosylimidazole-4-carboxamide (EICAR), mizoribine, and mycophenolic acid) in preventing viral replication in the lungs of BALB/c mice, a replication model for severe acute respiratory syndrome (SARS) infections (Subbarao, K., McAuliffe, J., Vogel, L., Fahle, G., Fischer, S., Tatti, K., Packard, M., Shieh, W.J., Zaki, S., Murphy, B., 2004. Prior infection and passive transfer of neutralizing antibody prevent replication of severe acute respiratory syndrome coronavirus (SARS-CoV) in the respiratory tract of mice. J. Virol. 78, 3572–3577). Ribavirin given at 75mg/kg 4h prior to virus exposure and then given twice daily for 3 days beginning at day 0 was found to increase virus lung titers and extend the length of time that virus could be detected in the lungs of mice. Other IMP dehydrogenase inhibitors administered near maximum tolerated doses using the same dosing regimen as for ribavirin were found to slightly enhance virus replication in the lungs. In addition, ribavirin treatment seemed also to promote the production of pro-inflammatory cytokines 4 days after cessation of treatment, although after 3 days of treatment ribavirin inhibited pro-inflammatory cytokine production in infected mice, significantly reducing the levels of the cytokines IL-1α, interleukin-5 (IL-5), monocyte chemotactic protein-1 (MCP-1), and granulocyte-macrophage colony stimulating factor (GM-CSF). These findings suggest that ribavirin may actually contribute to the pathogenesis of SARS-CoV by prolonging and/or enhancing viral replication in the lungs. By not inhibiting viral replication in the lungs of infected mice, ribavirin treatment may have provided a continual source of stimulation for the inflammatory response thought to contribute to the pathogenesis of the infection. Our data do not support the use of ribavirin or other IMP dehydrogenase inhibitors for treating SARS infections in humans.
Keywords: SARS-CoV; Ribavirin; IMP dehydrogenase inhibitor; BALB/C mouse; Enhancement; Infection; Severe acute respiratory syndrome; Coronavirus
Evaluation of methyl inosine monophosphate (MIMP) and peramivir activities in a murine model of lethal influenza A virus infection by Vasiliy P. Mishin; Frederick G. Hayden; Kathy L. Signorelli; Larisa V. Gubareva (pp. 64-68).
An inbred murine model (BALB/c) was utilized to assess the protective effect of the immunomodulator methyl inosine 5′-monophosphate (MIMP) against infection with influenza A/PR/8/34 (H1N1) virus. Contrary to the data reported for outbred mice (NMRI) infected with the aerosolized virus (Masihi, Hadden, 2003. J. Int. Immunopharmacol. 3, 1205–1215), there were no improvements in the outcomes of infection in the inbred animals treated with MIMP intranasally 1 day before the challenge and/or orally after the challenge for 5 days (up to 10mg/kg/day). Nevertheless, complete protection against lethality was afforded by the treatment with the neuraminidase inhibitor peramivir given once daily for 5 days after the challenge (10mg/kg/day). We speculate that the rapid progression of the disease in inbred mice caused by the intranasal challenge may render the MIMP-treatment ineffective. Our results emphasize the need for careful consideration of murine strains and routes of virus challenge in the design of experiments utilizing lethal influenza virus infection.
Keywords: Antiviral; Immunomodulator; Animal model; Neuraminidase inhibitor
The membranes’ role in the HIV-1 neutralizing monoclonal antibody 2F5 mode of action needs re-evaluation by Ana Salomé Veiga; Miguel A.R.B. Castanho (pp. 69-72).
2F5, a monoclonal antibody that neutralizes HIV-1 primary isolates, recognizes an epitope in the membrane proximal region of the glycoprotein gp41 ectodomain. It is believed that binding to the viral membrane is a step in the antibody mode of action, as usual in ligand membrane receptor interactions. We investigated the interaction of 2F5 with membrane model systems, namely large unilamellar vesicles, by means of fluorescence techniques. There were no significant interactions of 2F5 with model viral membranes or with model target cell membranes. Thus, the usual three-step ‘membrane catalysis’ method is not followed by 2F5 in its mode of action.
Keywords: MAb 2F5; HIV-1; Membrane; Fluorescence