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Antiviral Research (v.89, #2)

Notes to Authors (pp. co3).

Editorial Board (pp. ii).

Anthracene-based inhibitors of dengue virus NS2B–NS3 protease by Suzanne M. Tomlinson; Stanley J. Watowich (pp. 127-135).

Dengue virus (DENV) is a mosquito-borne flavivirus that has strained global healthcare systems throughout tropical and subtropical regions of the world. In addition to plaguing developing nations, it has re-emerged in several developed countries with recent outbreaks in the USA (), Australia (), Taiwan () and France (). DENV infection can cause significant disease, including dengue fever, dengue hemorrhagic fever, dengue shock syndrome, and death. There are no approved vaccines or antiviral therapies to prevent or treat dengue-related illnesses. However, the viral NS2B–NS3 protease complex provides a strategic target for antiviral drug development since NS3 protease activity is required for virus replication. Recently, we reported two compounds with inhibitory activity against the DENV protease in vitro and antiviral activity against dengue 2 (DEN2V) in cell culture (). Analogs of one of the lead compounds were purchased, tested in protease inhibition assays, and the data evaluated with detailed kinetic analyses. A structure activity relationship (SAR) identified key atomic determinants (i.e. functional groups) important for inhibitory activity. Four “second series” analogs were selected and tested to validate our SAR and structural models. Here, we report improvements to inhibitory activity ranging between ∼2- and 60-fold, resulting in selective low micromolar dengue protease inhibitors.

Keywords: Abbreviations; DENV; dengue virus; DEN2V; dengue 2 virus; NS; nonstructural; NS2B–NS3pro; NS3 protease domain with NS2B cofactor; DHF; dengue hemorrhagic fever; DSS; dengue shock syndrome; GKR; glycine–lysine–arginine; AMC; 7-amino-4-methylcoumarin; SAR; structure activity relationshipDengue virus; NS2B–NS3; Protease; Small-molecule inhibitor; Flavivirus

Hepatitis C virus complete life cycle screen for identification of small molecules with pro- or antiviral activity by Juliane Gentzsch; Bettina Hinkelmann; Lars Kaderali; Herbert Irschik; Rolf Jansen; Florenz Sasse; Ronald Frank; Thomas Pietschmann (pp. 136-148).

Infection with the hepatitis C virus represents a global public health threat given that an estimated 170 million individuals are chronically infected and thus at risk for cirrhosis and hepatocellular carcinoma. A number of direct antiviral molecules are in clinical development. However, side effects, drug resistance and viral genotype-specific differences in efficacy may limit these novel therapeutics. Therefore, a combination of well tolerated drugs with distinct mechanisms of action targeting different steps of the viral replication cycle will likely improve viral response rates and therapy success.To identify small molecules that interfere with different steps of the HCV replication cycle, we developed a novel dual reporter gene assay of the complete HCV life cycle and adapted it to 384-well high-throughput format. The system is based on a highly permissive Huh-7 cell line stably expressing a secreted luciferase. Using these cells and an efficient HCV luciferase reporter virus, perturbations of each step of the viral replication cycle as well as cell viability can be easily and quantitatively determined. The system was validated with a selected set of known HCV entry, replication and assembly inhibitors and then utilized to screen a library of small molecules derived from myxobacteria. Using this approach we identified a number of molecules that specifically inhibit HCV cell entry, or primarily virus assembly and release. Moreover, we also identified molecules that increase viral propagation. These compounds may be useful leads for development of novel HCV inhibitors and could be instrumental for the identification of as yet unknown host-derived viral resistance and dependency factors.

Keywords: Abbreviations; ApoB/E; apolipoprotein B/E; ConA; concanamycin A; HCV; Hepatitis C virus; HCVcc; cell culture-derived HCV; HCVpp; HCV pseudoparticles; HCV; _TCP; HCV trans-complemented particles; MLV; murine leukemia virus; peg-IFNα; pegylated interferon alpha; VSV; vesicular stomatitis virusHepatitis C virus; Chronic liver disease; HCV; Viral life cycle; Antiviral therapy; Tartrolon

Inhibition of HBV replication by theophylline by Zirui Zheng; Junyan Li; Jing Sun; Ting Song; Congwen Wei; Yanhong Zhang; Guirong Rao; Guangming Chen; DeChao Li; Gongming Yang; Bao Han; Shi Wei; Cheng Cao; Hui Zhong (pp. 149-155).

We have suggested recently that ATM-Rad3-Related (ATR) DNA damage signaling pathway, which responds to single-strand breaks in DNA, was activated in response to HBV infection. ATR knockdown cells showed decreased HBV DNA yields, implying HBV infection and replication activate and exploit the activated DNA damage response. Host cell proteins may constitute an attractive target for anti-HBV-1 therapeutics, since development of drug resistance against compounds targeting these cellular cofactor proteins is unlikely. In this study, we show that one of the clinically used compounds of ATR and ataxia telangiectasia-mutated (ATM) kinases inhibitor, theophylline (Tp), significantly reduced the yield of HBV DNA, HBsAg and HBeAg in HepG2215 cell culture system, furthermore, Tp could also suppress serum HBV DNA and HBsAg levels in the HBV-transgenic mice. Consistent with this result, immunohistology also showed reduced intensity of HBsAg staining on livers from Tp-treatment group. Taken together, these data indicated the feasibility of therapeutic approaches that target host cell proteins by inhibiting a cellular gene that was required for HBV replication and provided a potential approach for the prevention and treatment of HBV infection.

Keywords: Theophylline; DNA damage signaling pathway; HBV transgenic mice

Interferon plus Chinese herbs are associated with higher sustained virological response than interferon alone in chronic Hepatitis C: A meta-analysis of randomised trials by Sihai Zhao; Enqi Liu; Kena Wei; Shemin Lu; Yonglie Chu; Yafeng Li; Yanli Wang; Bingqiao Huang; Yulong Chen; Penghui Yang (pp. 156-164).

Traditional Chinese herbal therapies are widely used for the treatment of chronic hepatitis C (CHC) in Asia. The aim of this study was to perform a meta-analysis of randomised controlled trials (RCTs) comparing interferon therapies with Chinese herbal therapies and/or interferon plus Chinese herb therapies for the treatment of CHC.The Cochrane Central Register of Controlled Trials, Medline, Science Citation Index, EMBASE, China National Knowledge Infrastructure, Wanfang Database and China Biomedical Database were searched to identify RCTs that evaluated the virological response to interferon therapies, Chinese herbal therapies and interferon plus Chinese herb therapies in CHC patients. We statistically combined data using a random-effect meta-analysis according to the intention-to-treat principle.The literature search yielded 770 studies, and 26 RCTs comprising 1905 patients matched the selection criteria. Overall, the sustained virological response (SVR) was significantly higher in patients treated with interferon plus Chinese herbs than in patients treated with interferon alone (49% vs 33%, relative risk, 1.52; 95% confidence interval: 1.23–1.89; p<0.05). Combined therapies of interferon plus Chinese herb therapies were also superior to interferon therapies alone in achieving the end-of-treatment viral response (ETVR), and resulted in fewer relapses, fewer adverse events and more rapid alanine transaminase normalisation. Interferon therapies achieved higher ETVR than Chinese herbal therapies, but they yielded a similar SVR.The current evidence suggests that combined therapies of interferon plus Chinese herbs yielded a higher SVR, and resulted in fewer relapses and fewer adverse events than interferon therapies.

Keywords: Key words; Interferon; Chinese herbs; Chronic hepatitis C

Biodegradable nanogels for oral delivery of interferon for norovirus infection by Yunjeong Kim; Mahendra Thapa; Duy H. Hua; Kyeong-Ok Chang (pp. 165-173).

Norwalk virus (NV) replicon-harboring cells have provided an excellent tool to the development of antivirals. Previously we demonstrated that the expression levels of replicon RNA and proteins were significantly reduced in the presence of various interferons (IFNs) including IFN-α and IFN-γ in a dose-dependent manner in the NV replicon-harboring cells, and suggested that IFNs could be therapeutic options for norovirus infection. It was also demonstrated that innate immunity including IFNs is crucial in the replication and pathogenicity of murine norovirus (MNV) in vitro (RAW267.4 cells) and in vivo. IFNs have a short half-life in vitro and in vivo due to low stability. Thus it is important to have a good delivery system to improve the stability of IFNs. Nanogels are nanosized networks of chemically cross-linked polymers that swell in physiologic solutions and provide improved stability and bioavailability to drugs. We have synthesized nanogels based on cross-linked polyethyleneimine (PEI)-polyethylenglycol (PEG). The PEI/PEG nanogels were further acetylated (AcNg) to reduce cellular penetration and cytotoxicity. The IFN–AcNg complex was prepared by incubating two components together at 4°C and lyophilization. The IFN activity of IFN–AcNg was evaluated in the NV- and HCV-replicon-harboring cells and against MNV-1 in RAW267.4 cells in comparison to IFN without AcNg. The AcNg improved the stability of IFN stored at 4°C, and was well tolerated in the cells. Furthermore, the activity of IFN was significantly higher when combined with AcNg in the replicon-harboring cells and against MNV-1 in RAW267.4 cells. We concluded that AcNg may be pursued further as a vehicle for oral delivery of IFNs in norovirus infection.

Keywords: Antiviral; Interferon; Nanogel; Norwalk virus; Replicon-harboring cells; Murine norovirus

Three-dimensional analysis of combination effect of ellagitannins and acyclovir on herpes simplex virus types 1 and 2 by N. Vilhelmova; R. Jacquet; S. Quideau; A. Stoyanova; A.S. Galabov (pp. 174-181).

The effects of combinations of three nonahydroxyterphenoyl-bearing C-glucosidic ellagitannins (castalagin, vescalagin and grandinin) with acyclovir (ACV) on the replication of type-1 and type-2 herpes simplex viruses in MDBK cells were tested by the focus-forming units reduction test. Ellagitannins included in these combinations possess a high individual antiviral activity: selectivity index of castalagin and vescalagin versus HSV-1 was similar to that of ACV, and relatively lower against HSV-2. The three-dimensional analytical approach of Prichard and Shipman was used to evaluate the impact of drug–drug interactions. The combination effects of ellagitannins with acyclovir were markedly synergistic.

Keywords: HSV-1; HSV-2; Ellagitannins; ACV; Antiviral; Combination effect

Discordance rates between Trofile^® test and short-term virological response to maraviroc by Miguel Genebat; Ezequiel Ruiz-Mateos; Alejandro González-Serna; Ildefonso Pulido; Mª Ángeles Muñoz-Fernández; Sara Ferrando-Martínez; Manuel Leal (pp. 182-185).

Enhanced sensitivity Trofile^® (ES-Trofile^®) is the most frequently used technique to assay HIV tropism. A clinical approach to predict CCR5-antagonists efficacy, based on the virological response to a short-term maraviroc exposure (Maraviroc Clinical Test, MCT), has been recently reported. We compared the results of ES-Trofile^® with MCT in 47 HIV-infected patients, and a global discordance around 15% was observed between the phenotypic method and the clinical approach. Discordance results were mainly found in patients with an ES-Trofile^® reported as dual/mixed. These provocative results might have important clinical implications and should be considered in order to accurately prescribe treatment with CCR5 antagonists.

Keywords: Abbreviations; ES-Trofile; ^®; enhanced sensitivity Trofile; ^®; X4; CXCR4; MRV; maraviroc; MCT; Maraviroc Clinical Test; R5; CCR5; cART; combined antiretroviral therapy; D/M; dual/mixedTropism assay; Maraviroc; Clinical approach

Antiviral activity of ganciclovir and artesunate towards human cytomegalovirus in astrocytoma cells by Nathalie Schnepf; Jessie Corvo; Marie-José Sanson-Le Pors; Marie-Christine Mazeron (pp. 186-188).

Antimalarial drug artesunate inhibits cytomegalovirus (HCMV) replication in human fibroblasts. Astrocytes, the major cell type of the brain, support cytomegalovirus (HCMV) replication. The aim of the study was to assess the antiviral activity of artesunate in astrocytoma cell line U373MG in comparison with ganciclovir. The antiviral concentration inhibiting by 50% (IC₅₀) the synthesis of viral DNA was measured by real-time PCR in parallel in U373MG and MRC-5 cells. Reference HCMV strains susceptible and resistant to ganciclovir, and clinical isolates were tested. Ganciclovir and artesunate had similar activity in U373MG cells and MRC-5 fibroblasts. The artesunate IC₅₀s in U373MG cells (1.5–2.25μM) were at least 36-fold lower than the 50% cytotoxicity concentrations. Then, the anti-HCMV activity of artesunate was demonstrated in a cancer cell line.

Keywords: Cytomegalovirus; Artesunate; Ganciclovir; Antiviral activity; Astrocyte

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Antiviral Research (v.89, #2)