Ting-Chun Hung1, Alagie Jassey2, Ching-Hsuan Liu3, Chien-Ju Lin4, Chun-Ching Lin5, Shu Hui Wong6, Jonathan Y Wang7, Ming-Hong Yen8, Liang-Tzung Lin9. 1. Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Clinical Pathology, Chi Mei Medical Center, Tainan, Taiwan. 2. International Ph.D. Program in Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan. 3. Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan; Department of Microbiology & Immunology, Dalhousie University, Halifax, Nova Scotia, Canada. 4. School of Pharmacy, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan. 5. Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan; School of Pharmacy, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan. 6. International Master Program in Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan. 7. Department of Molecular Biosciences, The University of Texas at Austin, Austin, Texas, United States of America. 8. Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan; Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan. Electronic address: yen@kmu.edu.tw. 9. Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan; Department of Microbiology and Immunology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan. Electronic address: ltlin@tmu.edu.tw.
Abstract
BACKGROUND: Despite the advent of direct-acting antivirals (DAAs), HCV remains an important public health problem globally. There is at present no effective vaccine against the virus, and the DAAs in current use cannot prevent de novo infection, including in liver transplant setting wherein donor livers inevitably become re-infected. Developing inhibitors to HCV entry using nature-derived small molecules may help to expand/complement the current treatment options. PURPOSE: In this study, we explored the effect of the plant alkaloid berberine (BBR) on HCV early viral entry. METHODS: Cell culture-derived HCV (HCVcc), viral pseudoparticles bearing HCV glycoproteins (HCVpp), and entry-related assays were employed to assess BBR's bioactivity. Molecular docking was used to predict BBR-HCV glycoproteins interaction, and the compound's antiviral activity was confirmed against HCVcc infection of primary human hepatocytes (PHHs). RESULTS: BBR specifically impeded HCVcc attachment and entry/fusion steps without inactivating the free virus particles or affecting the expression of host cell entry factors and post-entry viral replication. BBR also effectively inhibited infection by viral pseudoparticles expressing HCV E1/E2 glycoproteins and molecular docking analysis pointed at potential interaction with HCV E2. Finally, BBR could suppress HCVcc infection of PHHs. CONCLUSIONS: We identified BBR as a potent HCV entry inhibitor, which merits further evaluation particularly for use in transplant setting against graft re-infection by HCV.
BACKGROUND: Despite the advent of direct-acting antivirals (DAAs), HCV remains an important public health problem globally. There is at present no effective vaccine against the virus, and the DAAs in current use cannot prevent de novo infection, including in liver transplant setting wherein donor livers inevitably become re-infected. Developing inhibitors to HCV entry using nature-derived small molecules may help to expand/complement the current treatment options. PURPOSE: In this study, we explored the effect of the plant alkaloid berberine (BBR) on HCV early viral entry. METHODS: Cell culture-derived HCV (HCVcc), viral pseudoparticles bearing HCV glycoproteins (HCVpp), and entry-related assays were employed to assess BBR's bioactivity. Molecular docking was used to predict BBR-HCV glycoproteins interaction, and the compound's antiviral activity was confirmed against HCVcc infection of primary human hepatocytes (PHHs). RESULTS: BBR specifically impeded HCVcc attachment and entry/fusion steps without inactivating the free virus particles or affecting the expression of host cell entry factors and post-entry viral replication. BBR also effectively inhibited infection by viral pseudoparticles expressing HCV E1/E2 glycoproteins and molecular docking analysis pointed at potential interaction with HCV E2. Finally, BBR could suppress HCVcc infection of PHHs. CONCLUSIONS: We identified BBR as a potent HCV entry inhibitor, which merits further evaluation particularly for use in transplant setting against graft re-infection by HCV.
Authors: Burtram C Fielding; Carlos da Silva Maia Bezerra Filho; Nasser S M Ismail; Damião Pergentino de Sousa Journal: Molecules Date: 2020-11-24 Impact factor: 4.411
Authors: Zhen-Zhen Wang; Kun Li; Anish R Maskey; Weihua Huang; Anton A Toutov; Nan Yang; Kamal Srivastava; Jan Geliebter; Raj Tiwari; Mingsan Miao; Xiu-Min Li Journal: FASEB J Date: 2021-04 Impact factor: 5.191