Niacin analogue, 6-Aminonicotinamide, a novel inhibitor of hepatitis B virus replication and HBsAg production
Background: Hepatitis B surface antigen (HBsAg) is one of the important clinical indexes for hepatitis B virus (HBV) infection diagnosis and sustained seroconversion of HBsAg is an indicator for functional cure. However, the level of HBsAg could not be reduced by interferons and nucleoside analogs e...
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| Published in | EBioMedicine Vol. 49; pp. 232 - 246 |
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| Main Authors | , , , , , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
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Netherlands
Elsevier B.V
01.11.2019
Elsevier |
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| Abstract | Background: Hepatitis B surface antigen (HBsAg) is one of the important clinical indexes for hepatitis B virus (HBV) infection diagnosis and sustained seroconversion of HBsAg is an indicator for functional cure. However, the level of HBsAg could not be reduced by interferons and nucleoside analogs effectively. Therefore, identification of a new drug targeting HBsAg is urgently needed.
Methods: In this study, 6-AN was screened out from 1500 compounds due to its low cytotoxicity and high antiviral activity. The effect of 6-AN on HBV was examined in HepAD38, HepG2-NTCP and PHHs cells. In addition, the antivirus effect of 6-AN was also identified in mouse model.
Findings: 6-AN treatment resulted in a significant decrease of HBsAg and other viral markers both in vitro and in vivo. Furthermore, we found that 6-AN inhibited the activities of HBV SpI, SpII and core promoter by decreasing transcription factor PPARα, subsequently reduced HBV RNAs transcription and HBsAg production.
Interpretation: We have identified a novel small molecule to inhibit HBV core DNA, HBV RNAs, HBsAg production, as well as cccDNA to a minor degree both in vitro and in vivo. This study may shed light on the development of a novel class of anti-HBV agent. |
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| AbstractList | Background: Hepatitis B surface antigen (HBsAg) is one of the important clinical indexes for hepatitis B virus (HBV) infection diagnosis and sustained seroconversion of HBsAg is an indicator for functional cure. However, the level of HBsAg could not be reduced by interferons and nucleoside analogs effectively. Therefore, identification of a new drug targeting HBsAg is urgently needed.
Methods: In this study, 6-AN was screened out from 1500 compounds due to its low cytotoxicity and high antiviral activity. The effect of 6-AN on HBV was examined in HepAD38, HepG2-NTCP and PHHs cells. In addition, the antivirus effect of 6-AN was also identified in mouse model.
Findings: 6-AN treatment resulted in a significant decrease of HBsAg and other viral markers both in vitro and in vivo. Furthermore, we found that 6-AN inhibited the activities of HBV SpI, SpII and core promoter by decreasing transcription factor PPARα, subsequently reduced HBV RNAs transcription and HBsAg production.
Interpretation: We have identified a novel small molecule to inhibit HBV core DNA, HBV RNAs, HBsAg production, as well as cccDNA to a minor degree both in vitro and in vivo. This study may shed light on the development of a novel class of anti-HBV agent. AbstractBackground: Hepatitis B surface antigen (HBsAg) is one of the important clinical indexes for hepatitis B virus (HBV) infection diagnosis and sustained seroconversion of HBsAg is an indicator for functional cure. However, the level of HBsAg could not be reduced by interferons and nucleoside analogs effectively. Therefore, identification of a new drug targeting HBsAg is urgently needed. Methods: In this study, 6-AN was screened out from 1500 compounds due to its low cytotoxicity and high antiviral activity. The effect of 6-AN on HBV was examined in HepAD38, HepG2-NTCP and PHHs cells. In addition, the antivirus effect of 6-AN was also identified in mouse model. Findings: 6-AN treatment resulted in a significant decrease of HBsAg and other viral markers both in vitro and in vivo. Furthermore, we found that 6-AN inhibited the activities of HBV SpI, SpII and core promoter by decreasing transcription factor PPARα, subsequently reduced HBV RNAs transcription and HBsAg production. Interpretation: We have identified a novel small molecule to inhibit HBV core DNA, HBV RNAs, HBsAg production, as well as cccDNA to a minor degree both in vitro and in vivo. This study may shed light on the development of a novel class of anti-HBV agent. Hepatitis B surface antigen (HBsAg) is one of the important clinical indexes for hepatitis B virus (HBV) infection diagnosis and sustained seroconversion of HBsAg is an indicator for functional cure. However, the level of HBsAg could not be reduced by interferons and nucleoside analogs effectively. Therefore, identification of a new drug targeting HBsAg is urgently needed.BACKGROUNDHepatitis B surface antigen (HBsAg) is one of the important clinical indexes for hepatitis B virus (HBV) infection diagnosis and sustained seroconversion of HBsAg is an indicator for functional cure. However, the level of HBsAg could not be reduced by interferons and nucleoside analogs effectively. Therefore, identification of a new drug targeting HBsAg is urgently needed.In this study, 6-AN was screened out from 1500 compounds due to its low cytotoxicity and high antiviral activity. The effect of 6-AN on HBV was examined in HepAD38, HepG2-NTCP and PHHs cells. In addition, the antivirus effect of 6-AN was also identified in mouse model.METHODSIn this study, 6-AN was screened out from 1500 compounds due to its low cytotoxicity and high antiviral activity. The effect of 6-AN on HBV was examined in HepAD38, HepG2-NTCP and PHHs cells. In addition, the antivirus effect of 6-AN was also identified in mouse model.6-AN treatment resulted in a significant decrease of HBsAg and other viral markers both in vitro and in vivo. Furthermore, we found that 6-AN inhibited the activities of HBV SpI, SpII and core promoter by decreasing transcription factor PPARα, subsequently reduced HBV RNAs transcription and HBsAg production.FINDINGS6-AN treatment resulted in a significant decrease of HBsAg and other viral markers both in vitro and in vivo. Furthermore, we found that 6-AN inhibited the activities of HBV SpI, SpII and core promoter by decreasing transcription factor PPARα, subsequently reduced HBV RNAs transcription and HBsAg production.We have identified a novel small molecule to inhibit HBV core DNA, HBV RNAs, HBsAg production, as well as cccDNA to a minor degree both in vitro and in vivo. This study may shed light on the development of a novel class of anti-HBV agent.INTERPRETATIONWe have identified a novel small molecule to inhibit HBV core DNA, HBV RNAs, HBsAg production, as well as cccDNA to a minor degree both in vitro and in vivo. This study may shed light on the development of a novel class of anti-HBV agent. Background: Hepatitis B surface antigen (HBsAg) is one of the important clinical indexes for hepatitis B virus (HBV) infection diagnosis and sustained seroconversion of HBsAg is an indicator for functional cure. However, the level of HBsAg could not be reduced by interferons and nucleoside analogs effectively. Therefore, identification of a new drug targeting HBsAg is urgently needed.Methods: In this study, 6-AN was screened out from 1500 compounds due to its low cytotoxicity and high antiviral activity. The effect of 6-AN on HBV was examined in HepAD38, HepG2-NTCP and PHHs cells. In addition, the antivirus effect of 6-AN was also identified in mouse model.Findings: 6-AN treatment resulted in a significant decrease of HBsAg and other viral markers both in vitro and in vivo. Furthermore, we found that 6-AN inhibited the activities of HBV SpI, SpII and core promoter by decreasing transcription factor PPARα, subsequently reduced HBV RNAs transcription and HBsAg production.Interpretation: We have identified a novel small molecule to inhibit HBV core DNA, HBV RNAs, HBsAg production, as well as cccDNA to a minor degree both in vitro and in vivo. This study may shed light on the development of a novel class of anti-HBV agent. Keywords: Hepatitis B virus, Hepatitis B surface antigen (HBsAg), 6-Aminonicotinamide (6-AN), Anti-HBV drugs Hepatitis B surface antigen (HBsAg) is one of the important clinical indexes for hepatitis B virus (HBV) infection diagnosis and sustained seroconversion of HBsAg is an indicator for functional cure. However, the level of HBsAg could not be reduced by interferons and nucleoside analogs effectively. Therefore, identification of a new drug targeting HBsAg is urgently needed. In this study, 6-AN was screened out from 1500 compounds due to its low cytotoxicity and high antiviral activity. The effect of 6-AN on HBV was examined in HepAD38, HepG2-NTCP and PHHs cells. In addition, the antivirus effect of 6-AN was also identified in mouse model. 6-AN treatment resulted in a significant decrease of HBsAg and other viral markers both in vitro and in vivo. Furthermore, we found that 6-AN inhibited the activities of HBV SpI, SpII and core promoter by decreasing transcription factor PPARα, subsequently reduced HBV RNAs transcription and HBsAg production. We have identified a novel small molecule to inhibit HBV core DNA, HBV RNAs, HBsAg production, as well as cccDNA to a minor degree both in vitro and in vivo. This study may shed light on the development of a novel class of anti-HBV agent. Background: Hepatitis B surface antigen (HBsAg) is one of the important clinical indexes for hepatitis B virus (HBV) infection diagnosis and sustained seroconversion of HBsAg is an indicator for functional cure. However, the level of HBsAg could not be reduced by interferons and nucleoside analogs effectively. Therefore, identification of a new drug targeting HBsAg is urgently needed. Methods: In this study, 6-AN was screened out from 1500 compounds due to its low cytotoxicity and high antiviral activity. The effect of 6-AN on HBV was examined in HepAD38, HepG2-NTCP and PHHs cells. In addition, the antivirus effect of 6-AN was also identified in mouse model. Findings: 6-AN treatment resulted in a significant decrease of HBsAg and other viral markers both in vitro and in vivo . Furthermore, we found that 6-AN inhibited the activities of HBV SpI, SpII and core promoter by decreasing transcription factor PPARα, subsequently reduced HBV RNAs transcription and HBsAg production. Interpretation: We have identified a novel small molecule to inhibit HBV core DNA, HBV RNAs, HBsAg production, as well as cccDNA to a minor degree both in vitro and in vivo . This study may shed light on the development of a novel class of anti-HBV agent. |
| Author | Law, Betty Yuen Kwan Yao, Fang-Long Hu, Jie-Li Jiang, Hui Xu, Hong-Yan Zhou, Hong-Zhong Ren, Fang Huang, Ai-Long Yang, Xiao Wong, Vincent Kam Wai Ren, Ji-Hua Yu, Hai-Bo Hu, Zhong-Wen Cai, Xue-Fei Cheng, Sheng-Tao Zhong, Shan Zhang, Wen-Lu Jia, Xiao-Jiong Chen, Juan |
| AuthorAffiliation | a The Key Laboratory of Molecular Biology of Infectious Diseases designated by the Chinese Ministry of Education, Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Room 617, College of Life Sciences Building, 1 YiXueYuan Road, YuZhong District, Chongqing 400016, China b State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Room 704a-02, Block H, Macau, China |
| AuthorAffiliation_xml | – name: b State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Room 704a-02, Block H, Macau, China – name: a The Key Laboratory of Molecular Biology of Infectious Diseases designated by the Chinese Ministry of Education, Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Room 617, College of Life Sciences Building, 1 YiXueYuan Road, YuZhong District, Chongqing 400016, China |
| Author_xml | – sequence: 1 givenname: Fang surname: Ren fullname: Ren, Fang organization: The Key Laboratory of Molecular Biology of Infectious Diseases designated by the Chinese Ministry of Education, Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Room 617, College of Life Sciences Building, 1 YiXueYuan Road, YuZhong District, Chongqing 400016, China – sequence: 2 givenname: Xiao surname: Yang fullname: Yang, Xiao organization: The Key Laboratory of Molecular Biology of Infectious Diseases designated by the Chinese Ministry of Education, Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Room 617, College of Life Sciences Building, 1 YiXueYuan Road, YuZhong District, Chongqing 400016, China – sequence: 3 givenname: Zhong-Wen surname: Hu fullname: Hu, Zhong-Wen organization: The Key Laboratory of Molecular Biology of Infectious Diseases designated by the Chinese Ministry of Education, Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Room 617, College of Life Sciences Building, 1 YiXueYuan Road, YuZhong District, Chongqing 400016, China – sequence: 4 givenname: Vincent Kam Wai surname: Wong fullname: Wong, Vincent Kam Wai organization: State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Room 704a-02, Block H, Macau, China – sequence: 5 givenname: Hong-Yan surname: Xu fullname: Xu, Hong-Yan organization: The Key Laboratory of Molecular Biology of Infectious Diseases designated by the Chinese Ministry of Education, Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Room 617, College of Life Sciences Building, 1 YiXueYuan Road, YuZhong District, Chongqing 400016, China – sequence: 6 givenname: Ji-Hua surname: Ren fullname: Ren, Ji-Hua organization: The Key Laboratory of Molecular Biology of Infectious Diseases designated by the Chinese Ministry of Education, Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Room 617, College of Life Sciences Building, 1 YiXueYuan Road, YuZhong District, Chongqing 400016, China – sequence: 7 givenname: Shan surname: Zhong fullname: Zhong, Shan organization: The Key Laboratory of Molecular Biology of Infectious Diseases designated by the Chinese Ministry of Education, Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Room 617, College of Life Sciences Building, 1 YiXueYuan Road, YuZhong District, Chongqing 400016, China – sequence: 8 givenname: Xiao-Jiong surname: Jia fullname: Jia, Xiao-Jiong organization: The Key Laboratory of Molecular Biology of Infectious Diseases designated by the Chinese Ministry of Education, Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Room 617, College of Life Sciences Building, 1 YiXueYuan Road, YuZhong District, Chongqing 400016, China – sequence: 9 givenname: Hui surname: Jiang fullname: Jiang, Hui organization: The Key Laboratory of Molecular Biology of Infectious Diseases designated by the Chinese Ministry of Education, Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Room 617, College of Life Sciences Building, 1 YiXueYuan Road, YuZhong District, Chongqing 400016, China – sequence: 10 givenname: Jie-Li surname: Hu fullname: Hu, Jie-Li organization: The Key Laboratory of Molecular Biology of Infectious Diseases designated by the Chinese Ministry of Education, Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Room 617, College of Life Sciences Building, 1 YiXueYuan Road, YuZhong District, Chongqing 400016, China – sequence: 11 givenname: Xue-Fei surname: Cai fullname: Cai, Xue-Fei organization: The Key Laboratory of Molecular Biology of Infectious Diseases designated by the Chinese Ministry of Education, Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Room 617, College of Life Sciences Building, 1 YiXueYuan Road, YuZhong District, Chongqing 400016, China – sequence: 12 givenname: Wen-Lu surname: Zhang fullname: Zhang, Wen-Lu organization: The Key Laboratory of Molecular Biology of Infectious Diseases designated by the Chinese Ministry of Education, Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Room 617, College of Life Sciences Building, 1 YiXueYuan Road, YuZhong District, Chongqing 400016, China – sequence: 13 givenname: Fang-Long surname: Yao fullname: Yao, Fang-Long organization: The Key Laboratory of Molecular Biology of Infectious Diseases designated by the Chinese Ministry of Education, Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Room 617, College of Life Sciences Building, 1 YiXueYuan Road, YuZhong District, Chongqing 400016, China – sequence: 14 givenname: Hai-Bo surname: Yu fullname: Yu, Hai-Bo organization: The Key Laboratory of Molecular Biology of Infectious Diseases designated by the Chinese Ministry of Education, Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Room 617, College of Life Sciences Building, 1 YiXueYuan Road, YuZhong District, Chongqing 400016, China – sequence: 15 givenname: Sheng-Tao surname: Cheng fullname: Cheng, Sheng-Tao organization: The Key Laboratory of Molecular Biology of Infectious Diseases designated by the Chinese Ministry of Education, Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Room 617, College of Life Sciences Building, 1 YiXueYuan Road, YuZhong District, Chongqing 400016, China – sequence: 16 givenname: Hong-Zhong surname: Zhou fullname: Zhou, Hong-Zhong organization: The Key Laboratory of Molecular Biology of Infectious Diseases designated by the Chinese Ministry of Education, Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Room 617, College of Life Sciences Building, 1 YiXueYuan Road, YuZhong District, Chongqing 400016, China – sequence: 17 givenname: Ai-Long surname: Huang fullname: Huang, Ai-Long organization: The Key Laboratory of Molecular Biology of Infectious Diseases designated by the Chinese Ministry of Education, Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Room 617, College of Life Sciences Building, 1 YiXueYuan Road, YuZhong District, Chongqing 400016, China – sequence: 18 givenname: Betty Yuen Kwan surname: Law fullname: Law, Betty Yuen Kwan email: yklaw@must.edu.mo organization: State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Room 704a-02, Block H, Macau, China – sequence: 19 givenname: Juan surname: Chen fullname: Chen, Juan email: chenjuan2014@cqmu.edu.cn organization: The Key Laboratory of Molecular Biology of Infectious Diseases designated by the Chinese Ministry of Education, Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Room 617, College of Life Sciences Building, 1 YiXueYuan Road, YuZhong District, Chongqing 400016, China |
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| Snippet | Background: Hepatitis B surface antigen (HBsAg) is one of the important clinical indexes for hepatitis B virus (HBV) infection diagnosis and sustained... AbstractBackground: Hepatitis B surface antigen (HBsAg) is one of the important clinical indexes for hepatitis B virus (HBV) infection diagnosis and sustained... Hepatitis B surface antigen (HBsAg) is one of the important clinical indexes for hepatitis B virus (HBV) infection diagnosis and sustained seroconversion of... |
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| SubjectTerms | 6-Aminonicotinamide (6-AN) 6-Aminonicotinamide - chemistry 6-Aminonicotinamide - pharmacology Advanced Basic Science Animals Anti-HBV drugs Biomarkers - blood Disease Models, Animal Hep G2 Cells Hepatitis B surface antigen (HBsAg) Hepatitis B Surface Antigens - metabolism Hepatitis B virus Hepatitis B virus - drug effects Hepatitis B virus - genetics Hepatitis B virus - physiology Humans Internal Medicine Mice, Inbred C57BL Mice, Transgenic Models, Biological Promoter Regions, Genetic - genetics Research paper Transcription, Genetic - drug effects Viremia - blood Virus Replication - drug effects |
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| Title | Niacin analogue, 6-Aminonicotinamide, a novel inhibitor of hepatitis B virus replication and HBsAg production |
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