Activity of compounds from Chinese herbal medicine Rhodiola kirilowii (Regel) Maxim against HCV NS3 serine protease.
Treatment of the chronic hepatitis C virus (HCV) infection is an unmet medical need, and the HCV NS3 serine protease (NS3-SP) has been used as an attractive target of antiviral screening against HCV. To find naturally chemical entities as lead compounds from which novel anti-HCV agents could be developed, bioassay-guided fractionation and isolation were performed on a crude ethanol extract from rhizomes of the Chinese medicinal herb Rhodiola kirilowii (Regel) Maxim using column chromatography (CC) techniques and in vitro inhibitory activity against HCV NS3-SP. The partition of the extract between water and different organic solvents led to the isolation and identification of 12 compounds in the ethyl acetate part which proved to be the most active. These compounds were tested for in vitro activity against HCV NS3-SP, among which four (-)-Epicatechin derivatives: 3,3'-Digalloylproprodelphinidin B2 (Rhodisin, 1); 3,3'-Digalloylprocyanidin B2 (2); (-)-Epigallocatechin-3-O-gallate (EGCG, 3); and (-)-Epicatechin-3-O-gallate (4, ECG) represented the most potent ones with IC(50) of 0.77, 0.91, 8.51, and 18.55 microM, respectively. Salidroside, the commonly known compounds, together with the other compounds showed no activity up to 100.0 microM. Methylation and acylation of the hydroxyl groups of 1-4 caused a decrease of activity. Cell viability and secreted alkaline phosphatase (SEAP) activity assays with 1-4 revealed little if any toxicity. These nonpeptide inhibitors of HCV NS3-SP might serve as potential candidate anti-HCV agents.
Zuo
Guoying
G
College of Chemistry and Molecular Engineering, Yangshengtang Nature Medicine Laboratory, Peking University, Beijing 100871, China.
Li
Zhengquan
Z
Chen
Lirong
L
Xu
Xiaojie
X
D000215:Acylation / Q000187:drug effects; D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology / Q000633:toxicity; D019556:COS Cells; D002522:Chlorocebus aethiops; D004365:Drugs, Chinese Herbal / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology* / Q000633:toxicity; D005960:Glucosides / Q000494:pharmacology; D016174:Hepacivirus / Q000187:drug effects / Q000201:enzymology; D006526:Hepatitis C / Q000201:enzymology*; D008745:Methylation / Q000187:drug effects; D010636:Phenols / Q000494:pharmacology; D027343:Rhizome; D029771:Rhodiola; D017361:Viral Nonstructural Proteins / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
D000998:Antiviral Agents; D004365:Drugs, Chinese Herbal; D005960:Glucosides; D010636:Phenols; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C009172:rhodioloside