title: Small molecule inhibitors of HCV replication from pomegranate.
abstract: Hepatitis C virus (HCV) is the causative agent of end-stage liver disease. Recent advances in the last decade in anti HCV treatment strategies have dramatically increased the viral clearance rate. However, several limitations are still associated, which warrant a great need of novel, safe and selective drugs against HCV infection. Towards this objective, we explored highly potent and selective small molecule inhibitors, the ellagitannins, from the crude extract of Pomegranate (Punica granatum) fruit peel. The pure compounds, punicalagin, punicalin, and ellagic acid isolated from the extract specifically blocked the HCV NS3/4A protease activity in vitro. Structural analysis using computational approach also showed that ligand molecules interact with the catalytic and substrate binding residues of NS3/4A protease, leading to inhibition of the enzyme activity. Further, punicalagin and punicalin significantly reduced the HCV replication in cell culture system. More importantly, these compounds are well tolerated ex vivo and'no observed adverse effect level' (NOAEL) was established upto an acute dose of 5000 mg/kg in BALB/c mice. Additionally, pharmacokinetics study showed that the compounds are bioavailable. Taken together, our study provides a proof-of-concept approach for the potential use of antiviral and non-toxic principle ellagitannins from pomegranate in prevention and control of HCV induced complications.
authors: Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore-560012, India.
authors: B Uma
authors: BU
authors: Reddy
authors: 1] Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore-560012, India [2].
authors: Ranajoy
authors: R
authors: Mullick
authors: 1] Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore-560012, India [2].
authors: Anuj
authors: A
authors: Kumar
authors: Molecular Biophysics Unit, Indian Institute of Science, Bangalore-560012, India.
authors: Govindarajan
authors: G
authors: Sudha
authors: Molecular Biophysics Unit, Indian Institute of Science, Bangalore-560012, India.
authors: Narayanaswamy
authors: N
authors: Srinivasan
authors: Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore-560012, India.
authors: Saumitra
authors: S
authors: Das
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002851:Chromatography, High Pressure Liquid; D004610:Ellagic Acid / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D016174:Hepacivirus / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D006526:Hepatitis C / Q000188:drug therapy / Q000821:virology; D054884:Host-Pathogen Interactions / Q000187:drug effects; D006801:Humans; D047348:Hydrolyzable Tannins / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D029561:Lythraceae / Q000737:chemistry*; D013058:Mass Spectrometry; D008807:Mice, Inbred BALB C; D008958:Models, Molecular; D015394:Molecular Structure; D008517:Phytotherapy; D011485:Protein Binding; D054852:Small Molecule Libraries / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects*; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D000998:Antiviral Agents; D004610:Ellagic Acid; D047348:Hydrolyzable Tannins; D054852:Small Molecule Libraries; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C115642:punicalagin; C115643:punicalin