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Resistance Analysis and Characterization of NITD008 As an Adenosine Analog Inhibitor Against Hepatitis C Virus

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Resistance Analysis and Characterization of NITD008 As an Adenosine Analog Inhibitor Against Hepatitis C Virus Antiviral Research 126 (2016) 43e54 Contents lists available at ScienceDirect Antiviral Research journal homepage: www.elsevier.com/locate/antiviral Resistance analysis and characterization of NITD008 as an adenosine analog inhibitor against hepatitis C virus * Jie Qing a, , Rui Luo a, Yaxin Wang b, Junxiu Nong a, Ming Wu a, Yan Shao a, Ruoyi Tang a, ** *** Xi Yu a, Zheng Yin b, , Yuna Sun c, a Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China b Center of Basic Molecular Science, Department of Chemistry, Tsinghua University, Beijing 100084, China c National Laboratory of Macromolecules, Institute of Biophysics, Chinese Academy of Science, Beijing 100101, China article info abstract Article history: Hepatitis disease caused by hepatitis C virus (HCV) is a severe threat to global public health, affecting Received 19 June 2015 approximately 3% of the world's population. Sofosbuvir (PSI-7977), a uridine nucleotide analog inhibitor Received in revised form targeting the HCV NS5B polymerase, was approved by FDA at the end of 2013 and represents a key step 19 December 2015 towards a new era in the management of HCV infection. Previous study identified NITD008, an adenosine Accepted 22 December 2015 nucleoside analog, as the specific inhibitor against dengue virus and showed good antiviral effect on Available online 24 December 2015 other flaviviruses or enteroviruses. In this report, we systematically analyzed the anti-HCV profile of NITD008, which was discovered to effectively suppress the replication of different strains of HCV in Keywords: HCV human hepatoma cells with a low nanomolar activity. On genotype 2a virus, or 2a, 1a, and 1b replicon > NITD008 cells, EC50 values were 8.7 nM, 93.3 nM, 60.0 nM and 67.2 nM, and selective index values were 2298.9, Nucleoside analog >214.4, >333.3, >298.5 respectively. We demonstrated that resistance to NITD008 was conferred by Polymerase mutation in NS5B (S282T) in the HCV infectious virus genotype 2a (JFH-1). Then, we compared the resistant profiles of NITD008 and PSI-7977, and found that the folds change of EC50 of NITD008 to full replicon cells containing mutation S282T was much bigger than PSI-7977(folds 76.50 vs. 4.52). Analysis of NITD008 cross-resistance against previously reported NS5B drug-selected mutations showed that the resistance pattern of NITD008 was not completely similar to PSI-7977, and meanwhile, S282T resistant mutation to NITD008 emerge more easily in cell culture than PSI-7977. Interestingly, NITD008 displayed significant synergistic effects with the NS5B polymerase inhibitor PSI-7977, however, only additive ef- fects with alpha interferon (IFNa-2b), ribavirin, and an NS3 protease inhibitor. These results verify that NITD008 is an effective analog inhibitor against hepatitis C virus and a good research tool as a supple- ment to other types of nucleoside analogs. © 2015 Elsevier B.V. All rights reserved. 1. Introduction year due to HCV-related complications (Lavanchy, 2009; Pol et al., 2012). Chronic infection with hepatitis C virus (HCV) has been reported Chronic HCV infection in many patients is curable; however, the to affect 170 million people worldwide, and hepatitis C not only existing standard of care (SOC) that is based on parenteral admin- seriously affects the function of the patient's liver but also triggers istration of pegylated interferon-a (PEG-IFN-a), together with the liver fibrosis and cirrhosis that may eventually lead to hepatocel- oral broad-spectrum antiviral ribavirin (RBV), has a number of lular carcinoma (Lavanchy, 2009). The World Health Organization deficiencies (Devogelaere et al., 2012). The treatment requires a estimates that there are 350,000 people in the world who die each period of up to 48 weeks, depending on the HCV genotype, and the efficacy shows distinct variations across HCV genotypes. Genotype 1, which predominates in Europe, Japan, and the United States, is * Corresponding author. particularly difficult to treat, and the rates of sustained virologic ** Corresponding author. response (SVR) post treatment seldom exceed 50% for genotype 1 *** Corresponding author. with IFN-a/RBV (Strader et al., 2004). Two direct-acting antiviral E-mail addresses: [email protected] (J. Qing), [email protected]. cn (Z. Yin), [email protected] (Y. Sun). (DAA) inhibitors of the HCV NS3 protease, boceprevir and http://dx.doi.org/10.1016/j.antiviral.2015.12.010 0166-3542/© 2015 Elsevier B.V. All rights reserved. 44 J. Qing et al. / Antiviral Research 126 (2016) 43e54 Fig. 1. The chemical structures of the HCV NS5B polymerase inhibitors, NITD008, PSI-7977 and the NS3/4A protease inhibitor telaprevir. telaprevir, were approved in 2011 for use in combination with IFN- et al., 2012; Jacobson et al., 2011). a/RBV for genotype 1 treatment. The using of either of these in- The U.S. Food and Drug Administration approved two further hibitors with IFN-a/RBV elevated the SVR rates to approximately DAA inhibitors in late 2013. Sofosbuvir (PSI-7977), a uridine analog 70% in treatment-naive patients (Bacon et al., 2011; Devogelaere inhibitor of the HCV NS5B RNA-dependent RNA polymerase (RdRp), Fig. 2. Antiviral and cytotoxic activities of NITD008 and telaprevir against HCV genotypes. The inhibitory effect of NITD008 and telaprevir to the proliferation of the JFH-1 virus (A), JFH-1 full replicon (B), H77 replicon (C), and Con1 replicon (D) by dose-dependence was evaluated at 48 h posttreatment by detecting the luciferase expression of the reporter gene, and (E) The cytotoxicity was evaluated by the incubation of Huh7.5.1 cells with the indicated concentration of NITD008. At 48 h posttreatment, the viability of the treated cells was measured by a WST-1 assay and presented as a percentage of the untreated cells. The results are reported as the average ± SD from three independent experiments that were performed in triplicate. J. Qing et al. / Antiviral Research 126 (2016) 43e54 45 Fig. 3. Selection and characterization of NITD008-resistant HCV virus. (A) The scheme used for the selection of a NITD008-resistant JFH-1 recombinant virus, which is con- structed by inserting an EGFP reporter gene into the C-terminus of NS5A of the JFH-1 genome. The Huh7.5.1 cells were infected by a JFH-1 recombinant virus in the presence of gradually increasing concentrations of NITD008 and passaged every 2 or 3 days, and the arrow symbol indicated that the supernatant treated by NITD008 would infect the native Huh7.5.1 cells. The concentrations of NITD008 that correspond to different passages during the selection are indicated. (B) A characterization of the resistance phenotypes of the JFH-1 resistant virus. The indicated concentrations of NITD008 were added to the Huh7.5.1 cells infected by HCV at an MOI of 0.5. (C) The HCV proliferation in the presence or absence of NITD008 was quantified at 48 h p.i. by the EGFP expression. (D) The frequency of amino acid changes in the HCV genome that emerged during the selection with NITD008 in the Huh7.5.1 cells infected by the JFH-1 recombinant virus. is used in combination with IFN-a/RBV for the treatment of geno- However, both IFN-a/RBV and DAA have severe and treatment type 1 and 4, with RBV alone for genotype 2 and 3(Dieterich et al., limiting side effects, for example IFN-a/RBV results in a range of 2014; Jonckers et al., 2014; Lam et al., 2012; Lawitz and Gane, 2013). side effects, including anemia, flu-like symptoms and depression in Simeprevir, another NS3 protease inhibitor, is used with IFN-a/RBV a significant minority of patients; meanwhile, telaprevir and for genotype 1 treatment (Dieterich et al., 2014; Zeuzem et al., boceprevir are associated with a number of toxicities, such as rash, 2014). Both of these newer agents, in combination with IFN-a/ pruritus and the exacerbation of treatment-related anemia (Manns RBV, have further improved the genotype 1 treatment responses, et al., 2007). Although sofosbuvir as a uridine nucleotide analog has with treatment-naive SVR rates of approximately 80% for sime- become commercially available for the treatment of chronic HCV previr and approximately 90% for sofosbuvir. infection, we are highly interested to know whether other types of 46 J. Qing et al. / Antiviral Research 126 (2016) 43e54 nucleotide analogs could exert a good inhibitory effect on HCV and inhibitors. to study the drug resistance and other differences between PSI- 7977 and other potential nucleotide analogs. 2. Materials and methods NITD008 is an adenosine nucleoside analog that contains a carbon substitution for N-7 of the purine and an acetylene at the 2' 2.1. Compounds and reagents position of ribose (Yin et al., 2009). NITD008 has been reported to inhibit viruses within the family Flaviviridae, such as dengue virus NITD008 and PSI-7977 were synthesized according to a pub- (DENV), West Nile virus (WNV), yellow fever virus (YFV), or lished procedure (Jonckers et al., 2014; Yin et al., 2009). Telaprevir Enterovirus 71 (EV71) (Deng et al., 2014; Yin et al., 2009). Notably, was generously provided by GinkgoPharma, China. Recombinant the selection of resistant virus was attempted by continuous human Interferon alpha-2b (IFNa-2b, An Dafen) was purchased culturing of DENV or WNV on BHK-21 or Vero cells, and no resistant from Anhui Anke Biotechnology Group, China. Ribavirin was pur- virus was discovered (Yin et al., 2009). In this study, we charac- chased from Sigma. The inhibitors were initially dissolved in DMSO, terized the anti-HCV activity of NITD008 across broad HCV geno- and stock solutions were stored at À20 C. Immediately before types and systematically studied the resistance to NITD008 and the addition, these compounds were diluted to the desired concen- synergistic effects of NITD008, PSI-7977 and other anti-HCV trations using Dulbecco's modified Eagle's medium (DMEM, Gibco) Fig.
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