Medicinal Chemistry Research

, Volume 21, Issue 7, pp 1179–1187

Antiviral effects of three novel derivatives of adefovir on the replication of hepatitis B virus

Original Research

Abstract

Nucleoside/tide analogs are now widely used for treatment of chronic hepatitis B (CHB). However, available nucleoside/tide analogs for treatment of CHB usually have limited therapeutic effect and potential adverse effects on CHB patients. We evaluated the anti-HBV effects of three novel derivatives (compounds 1, 4, and 8) of adefovir on the replication of hepatitis B virus (HBV) and determined their cytotoxicity. The effects of those compounds on the replication of human HBV in the HepG2 2.2.15 cell line and duck HBV in infected ducks were characterized by measuring the extracellular and intracellular HBV DNA using the quantitative real-time PCR and Southern blot assays. Their cytotoxicities against HepG2 cells were evaluated by MTT and measuring the contents of mitochondrial DNA using the dot blot assay. We found that all of the compounds inhibited the production of HBV in a dose-dependent manner, similar to that of adefovir dipivoxil. Furthermore, treatment with any of the compounds reduced significantly the replication of DHBV in ducks, accompanied by a significant reduction of inflammation in the livers, and the compound 1 appeared to be a fast-acting and long-lasting anti-DHBV reagent. Importantly, all of the compounds showed little cytotoxicity against HepG2 cells, even at a concentration of 1 mM. Collectively, those novel derivatives of adefovir had potent anti-HBV activity with little adverse effect and may be therapeutic candidates for potential clinical studies.

Keywords

Hepatitis B virus Nucleoside/tide analogs Antiviral drugs Ducks 

References

  1. Baek HJ, Lim SC, Kitisin K, Jogunoori W, Tang Y, Marshall MB, Mishra B, Kim TH, Cho KH, Kim SS, Mishra L (2008) Hepatocellular cancer arises from loss of transforming growth factor beta signaling adaptor protein embryonic liver fodrin through abnormal angiogenesis. Hepatology 48:1128–1137PubMedCrossRefGoogle Scholar
  2. Chan C, Abu-Raddad E, Golor G, Watanabe H, Sasaki A, Yeo KP, Soon D, Sinha VP, Flanagan SD, He MM, Wise SD (2005) Clinical pharmacokinetics of alamifovir and its metabolites. Antimicrob Agents Chemother 49:1813–1822PubMedCrossRefGoogle Scholar
  3. Chang TT, Lai CL (2006) Hepatitis B virus with primary resistance to adefovir. N Engl J Med 355:322–323 (author reply 323)PubMedCrossRefGoogle Scholar
  4. Chen CH, Cheng YC (1989) Delayed cytotoxicity and selective loss of mitochondrial DNA in cells treated with the anti-human immunodeficiency virus compound 2′,3′-dideoxycytidine. J Biol Chem 264:11934–11937PubMedGoogle Scholar
  5. Chevallier M, Guerret S, Chossegros P, Gerard F, Grimaud JA (1994) A histological semiquantitative scoring system for evaluation of hepatic fibrosis in needle liver biopsy specimens: comparison with morphometric studies. Hepatology 20:349–355PubMedCrossRefGoogle Scholar
  6. Cui L, Yoon S, Schinazi RF, Sommadossi JP (1995) Cellular and molecular events leading to mitochondrial toxicity of 1-(2-deoxy-2-fluoro-1-beta-d-arabinofuranosyl)-5-iodouracil in human liver cells. J Clin Invest 95:555–563PubMedCrossRefGoogle Scholar
  7. Delaney WEt, Edwards R, Colledge D, Shaw T, Furman P, Painter G, Locarnini S (2002) Phenylpropenamide derivatives AT-61 and AT-130 inhibit replication of wild-type and lamivudine-resistant strains of hepatitis B virus in vitro. Antimicrob Agents Chemother 46:3057–3060PubMedCrossRefGoogle Scholar
  8. Dienstag JL (2008) Hepatitis B virus infection. N Engl J Med 359:1486–1500PubMedCrossRefGoogle Scholar
  9. Dusheiko G, Antonakopoulos N (2008) Current treatment of hepatitis B. Gut 57:105–124PubMedCrossRefGoogle Scholar
  10. Fan YF, Lu CC, Chen WC, Yao WJ, Wang HC, Chang TT, Lei HY, Shiau AL, Su IJ (2001) Prevalence and significance of hepatitis B virus (HBV) pre-S mutants in serum and liver at different replicative stages of chronic HBV infection. Hepatology 33:277–286PubMedCrossRefGoogle Scholar
  11. Feld JJ, Colledge D, Sozzi V, Edwards R, Littlejohn M, Locarnini SA (2007) The phenylpropenamide derivative AT-130 blocks HBV replication at the level of viral RNA packaging. Antiviral Res 76:168–177PubMedCrossRefGoogle Scholar
  12. Funk A, Mhamdi M, Hohenberg H, Heeren J, Reimer R, Lambert C, Prange R, Sirma H (2008) Duck hepatitis B virus requires cholesterol for endosomal escape during virus entry. J Virol 82:10532–10542PubMedCrossRefGoogle Scholar
  13. Gaillard RK, Barnard J, Lopez V, Hodges P, Bourne E, Johnson L, Allen MI, Condreay P, Miller WH, Condreay LD (2002) Kinetic analysis of wild-type and YMDD mutant hepatitis B virus polymerases and effects of deoxyribonucleotide concentrations on polymerase activity. Antimicrob Agents Chemother 46:1005–1013PubMedCrossRefGoogle Scholar
  14. Girard FC, Ottink OM, Ampt KA, Tessari M, Wijmenga SS (2007) Thermodynamics and NMR studies on duck, heron and human HBV encapsidation signals. Nucleic Acids Res 35:2800–2811PubMedCrossRefGoogle Scholar
  15. Gordon M (1996) Severe toxicity of fialuridine (FIAU). N Engl J Med 334:1136–1137 (author reply 1137–1138)PubMedGoogle Scholar
  16. Kamiya N, Kubota A, Iwase Y, Sekiya K, Ubasawa M, Yuasa S (2002) Antiviral activities of MCC-478, a novel and specific inhibitor of hepatitis B virus. Antimicrob Agents Chemother 46:2872–2877PubMedCrossRefGoogle Scholar
  17. Lai CL, Yuen MF (2008) Chronic hepatitis B—new goals, new treatment. N Engl J Med 359:2488–2491PubMedCrossRefGoogle Scholar
  18. Lai CL, Gane E, Liaw YF, Hsu CW, Thongsawat S, Wang Y, Chen Y, Heathcote EJ, Rasenack J, Bzowej N, Naoumov NV, Di Bisceglie AM, Zeuzem S, Moon YM, Goodman Z, Chao G, Constance BF, Brown NA (2007) Telbivudine versus lamivudine in patients with chronic hepatitis B. N Engl J Med 357:2576–2588PubMedCrossRefGoogle Scholar
  19. Lok AS (2005) The maze of treatments for hepatitis B. N Engl J Med 352:2743–2746PubMedCrossRefGoogle Scholar
  20. Ono-Nita SK, Kato N, Shiratori Y, Carrilho FJ, Omata M (2002) Novel nucleoside analogue MCC-478 (LY582563) is effective against wild-type or lamivudine-resistant hepatitis B virus. Antimicrob Agents Chemother 46:2602–2605PubMedCrossRefGoogle Scholar
  21. Opii WO, Sultana R, Abdul HM, Ansari MA, Nath A, Butterfield DA (2007) Oxidative stress and toxicity induced by the nucleoside reverse transcriptase inhibitor (NRTI)-2′,3′-dideoxycytidine (ddC): relevance to HIV-dementia. Exp Neurol 204:29–38PubMedCrossRefGoogle Scholar
  22. Prince AM (1996) Severe toxicity of fialuridine (FIAU). N Engl J Med 334:1136 (author reply 1137–1138)PubMedGoogle Scholar
  23. Quan DJ, Peters MG (2004) Antiviral therapy: nucleotide and nucleoside analogs. Clin Liver Dis 8:371–385PubMedCrossRefGoogle Scholar
  24. Schultz U, Grgacic E, Nassal M (2004) Duck hepatitis B virus: an invaluable model system for HBV infection. Adv Virus Res 63:1–70PubMedCrossRefGoogle Scholar
  25. Sekiya K, Takashima H, Ueda N, Kamiya N, Yuasa S, Fujimura Y, Ubasawa M (2002) 2-Amino-6-arylthio-9-[2-(phosphonomethoxy)ethyl] purine bis(2,2,2-trifluoroethyl) esters as novel HBV-specific antiviral reagents. J Med Chem 45:3138–3142PubMedCrossRefGoogle Scholar
  26. Soon DK, Lowe SL, Teng CH, Yeo KP, McGill J, Wise SD (2004) Safety and efficacy of alamifovir in patients with chronic hepatitis B virus infection. J Hepatol 41:852–858PubMedCrossRefGoogle Scholar
  27. Wang JQ, Fei X, Gardner TA, Hutchins GD, Zheng QH (2005) Synthesis of 2-amino-6-(4-[11C]methoxyphenylthio)-9-[2-(phosphonomethoxy)ethyl] purine bis(2,2,2-trifluoroethyl) ester as a novel potential PET gene reporter probe for HBV and HSV-tk in cancers. Bioorg Med Chem 13:549–556PubMedCrossRefGoogle Scholar
  28. Wu LL, Yang XB, Huang ZM, Liu HZ, Wu GX (2007) In vivo and in vitro antiviral activity of hyperoside extracted from Abelmoschus manihot (L) medik. Acta Pharmacol Sin 28:404–409PubMedCrossRefGoogle Scholar
  29. Yamada H, Suryanarayanan R (2007) X-ray powder diffractometry of intact film coated tablets—an approach to monitor the physical form of the active pharmaceutical ingredient during processing and storage. J Pharm Sci 96:2029–2036PubMedCrossRefGoogle Scholar
  30. Yuen MF, Tanaka Y, Shinkai N, Poon RT, But DY, Fong DY, Fung J, Wong DK, Yuen JC, Mizokami M, Lai CL (2008) Risk for hepatocellular carcinoma with respect to hepatitis B virus genotypes B/C, specific mutations of enhancer II/core promoter/precore regions and HBV DNA levels. Gut 57:98–102PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Department of Hepatologythe First Hospital, Jilin UniversityChangchunChina
  2. 2.Department of China-West MedicineTumor Hospital of Jilin ProvinceChangchunChina
  3. 3.Department of Sanitary ChemistrySchool of Public Health, Jilin UniversityChangchunChina
  4. 4.Institute of DrugsAcademy of Military Medical SciencesBeijingChina

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