piperidines and Hepatitis-C

Aloperine, a natural alkaloid isolated from the Chinese traditional herb Sophora alopecuroides, is a broad-spectrum antiviral agent with anti-inflammatory activity. Here, we found that aloperine effectively inhibited hepatitis C virus (HCV) propagation in Huh7.5 cells and primary human hepatocytes without cytotoxicity, and it blocked HCV cell-to-cell viral transmission. The antiviral mechanism evidence demonstrated that aloperine inhibits HCV internalisation from endocytosis to the membrane fusion process, and the target may be associated with host factors. Aloperine additively inhibited HCV propagation with direct-acting antivirals (DAAs) and was effective against HCV variants resistant to known DAAs. Therefore, aloperine might be a natural lead compound for the development of innovative antivirals, and the combined use of aloperine with DAAs might contribute to eliminating liver diseases caused by HCV infection.

Topics: Antiviral Agents; Cell Line; Endocytosis; Hepacivirus; Hepatitis C; Hepatocytes; Host-Pathogen Interactions; Humans; Membrane Fusion; Piperidines; Quinolizidines; Virus Internalization; Virus Replication

Several novel compounds were found to be potent inhibitors of the HCV (JFH-1 isolate) infection in vitro. Human serum did not significantly reduce antiviral activity of the lead compound, AVR560 (< 4-fold). The immunohistochemistry studies with the Huh7 cell line, infectable with the HCV (JFH-1 strain), demonstrated that AVR560 inhibited the early steps of viral infection and blocked the spread of the HCV infection in tissue culture. The cytotoxicity in Huh7 and Vero-76 cell lines was mild. AVR560 proved to be a specific HCV inhibitor and exhibited no activity against other flaviviruses such as yellow fever (strain 17D), West Nile (strain NY99), and dengue (New Guinea type 2) in in vitro infection experiments. AVR560 also did not inhibit any of the tested human CYP450 isozymes (3A4, 1A2, 2C19 and 2D6). In the pharmacokinetic studies in mice, rats and dogs, favorable pharmacokinetic profiles and good oral bioavailability were observed for AV560. Further pre-clinical studies with this novel HCV inhibitor are in progress.

Topics: Animals; Antiviral Agents; Cell Line, Tumor; Cell Survival; Chlorocebus aethiops; Cytochrome P-450 Enzyme System; Dengue Virus; Dogs; Drug Evaluation, Preclinical; Hepacivirus; Hepatitis C; Hepatocytes; Humans; Mice; Piperazines; Piperidines; Rats; Vero Cells; Virus Internalization; Virus Replication; West Nile virus; Yellow fever virus

Patients receiving interferon-alpha often experience symptoms such as upper abdominal discomfort, anorexia, and nausea, which suggest a delay in gastric emptying. Reduction of the dosages of interferon-alpha or even interruption of the treatment is sometimes required because of these symptoms. The present study was designed to investigate the effect of interferon-alpha on gastric emptying and to evaluate the effects of cisapride on gastric emptying and upper abdominal symptoms during interferon-alpha therapy.. Gastric emptying in 14 patients with chronic hepatitis C was estimated by the sulfamethizole capsule method before and 1 and 2 weeks after the beginning of interferon-alpha (6 million U/day) therapy.. Before therapy none of the patients complained of upper abdominal symptoms, and all had normal gastric emptying. Interferon treatment delayed gastric emptying in 12 of the patients and induced discomfort and anorexia in 9 of the patients. The administration of cisapride reversed the delayed gastric emptying in six of seven patients and relieved abdominal discomfort and anorexia.. These findings indicate that interferon-alpha delays gastric emptying and suggest that cisapride administration corrects the delayed gastric emptying and relieves the abdominal symptoms associated with interferon-alpha therapy.

Topics: Antiviral Agents; Cisapride; Dyspepsia; Female; Gastric Emptying; Gastrointestinal Agents; Hepatitis C; Hepatitis, Chronic; Humans; Interferon Type I; Male; Middle Aged; Piperidines; Recombinant Proteins; Sulfamethizole