Small molecule inhibitors of HCV replication from Pomegranate

• Published in: Scientific reports Vol. 4; no. 1; p. 5411
• Main Authors: Reddy, B. Uma, Mullick, Ranajoy, Kumar, Anuj, Sudha, Govindarajan, Srinivasan, Narayanaswamy, Das, Saumitra
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 24.06.2014; Nature Publishing Group
• Subjects: 13; 13/106; 140/58; 631/326/596/1905; 631/92/613; 82; 82/29; 82/83; Animals; Antiviral agents; Antiviral Agents - chemistry; Antiviral Agents - metabolism; Antiviral Agents - pharmacology; Cell culture; Cell Line, Tumor; Chromatography, High Pressure Liquid; Computer applications; Ellagic acid; Ellagic Acid - chemistry; Ellagic Acid - metabolism; Ellagic Acid - pharmacology; Hepacivirus - drug effects; Hepacivirus - enzymology; Hepacivirus - genetics; Hepatitis C; Hepatitis C - drug therapy; Hepatitis C - virology; Host-Pathogen Interactions - drug effects; Humanities and Social Sciences; Humans; Hydrolyzable Tannins - chemistry; Hydrolyzable Tannins - metabolism; Hydrolyzable Tannins - pharmacology; Liver diseases; Mass Spectrometry; Mice, Inbred BALB C; Models, Molecular; Molecular Structure; multidisciplinary; Pharmacokinetics; Phytotherapy; Proteases; Protein Binding; Proteinase; Punica granatum; Punicaceae - chemistry; Replication; Science; Small Molecule Libraries - chemistry; Small Molecule Libraries - metabolism; Small Molecule Libraries - pharmacology; Viral Nonstructural Proteins - antagonists & inhibitors; Viral Nonstructural Proteins - chemistry; Viral Nonstructural Proteins - metabolism; Virus Replication - drug effects
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep05411

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.