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To study the efficacy of a polyoxometalate, Cs 2 K 4 Na[SiW 9 Nb 3 O 40 ]·H 2 O, as an antiviral treatment in HBV transgenic mice. HBV transgenic mice were treated with Cs 2 K 4 Na[SiW 9 Nb 3 O 40 ]·H 2 O by intragastric administration. Adefovir and distilled water were administered as controls. Serum HBV DNA, liver HBV RNA levels were measured by quantitative RT-PCR. Serum HBsAg levels were measured by ELISA. The hepatitis B virus surface antigen (HBsAg) in liver cells was detected by immunohistochemistry (IHC). Pathological changes in the liver tissues were also observed by light and electron microscopy. Cs 2 K 4 Na[SiW 9 Nb 3 O 40 ]·H 2 O significantly decreased serum HBsAg and HBV DNA levels. Cs 2 K 4 Na[SiW 9 Nb 3 O 40 ]·H 2 O resulted in a 98% decrease in serum HBV DNA at 28 days, from 4.3 log 10 copies/ml at baseline to 2.5 log 10 copies/ml after treatment, and the inhibition rate of HBV DNA was higher than ADV at the same dose. The HBV replication levels in each group slightly increased at 7 days after withdrawal, but rebounded slightly more in the Cs 2 K 4 Na[SiW 9 Nb 3 O 40 ]·H 2 O treatment group compared to the H 2 O control group (p < .05). There were no differences in HBV RNA levels. No significant differences were observed in the pathology, but there were decreased HBsAg levels in the Cs 2 K 4 Na[SiW 9 Nb 3 O 40 ]·H 2 O-treated group compared to the control group. The results demonstrated that Cs 2 K 4 Na[SiW 9 Nb 3 O 40 ]·H 2 O displayed potent anti-HBV activity in HBV transgenic mice and supported for future clinic study., (© 2019 Wiley Periodicals, Inc.)

Bovine viral diarrhea virus (BVDV) fall into cytopathic (CP) and noncytopathic (NCP) biotypes, based on their ability to kill cultured cells. NCP-BVDV can not be titrated by conventional means as used for CP-BVDV, which has impeded the identification of antiviral drugs targeting NCP-BVDV virus strains. In this study, the application of an immunoperoxidase assay in the screening of antiviral drugs was tested using two known BVDV inhibitors, ribavirin and ammonium chloride (NH4Cl). Phospholipase C inhibitor U73122 was identified to affect BVDV infection by using this immunoperoxidase assay. In addition, the results of immunoperoxidase assay were validated by real-time PCR. Taken together, the immunoperoxidase assay is a useful and versatile method suitable for antiviral drug screening targeting NCP-BVDV., (Copyright © 2018 International Alliance for Biological Standardization. Published by Elsevier Ltd. All rights reserved.)

Objective: Yimitasvir phosphate, an inhibitor of nonstructural protein 5A (NS5A) replication complex of hepatitis C virus (HCV), was evaluated in a double-blind, placebo-controlled, parallel, multiple-dose study., Methods: Twenty-four patients with chronic HCV genotype 1 infection were randomized to receive a 7-day course of yimitasvir phosphate at daily doses of 30, 100 or 200 mg or placebo. Antiviral efficacy, resistance profile, pharmacokinetics (PK), safety and tolerability were assessed., Key Findings: The maximal reduction in HCV RNA from baseline was 5.17 log 10 IU/ml. However, most patients experienced viral rebound on or before day 3 after yimitasvir treatment was initiated. The PK profile revealed median peak plasma concentrations at 4-12 h postdose and a mean terminal half-life of 14.47-17.09 h, the basis for daily dosing. Steady drug state was achieved following 5 days of daily dosing. The accumulation rate was low (1.29-1.73). There were no significant alterations in vital signs and laboratory findings among all participants., Conclusions: This study shows that yimitasvir phosphate was well tolerated, and the PK profile supported daily dosing regimens. A 1-week (7-day) treatment course led to a quick and significant reduction in HCV RNA level in this cohort with HCV GT-1 infection., (© 2018 Royal Pharmaceutical Society.)

Aims: A recombinant human serum albumin-interferon alpha2a fusion protein (rHSA/IFNα2a) is expected to extend the half-life of IFNα2a. This study aims to evaluate the tolerability, safety and efficacy of rHSA/IFNα2a., Methods: This is an open, randomized, positive control, multiple-dose ascending Phase Ib study. A panel of 32 treatment naïve and non-cirrhotic chronic hepatitis B patients were divided into four cohorts, and each received 600, 750 or 900 μg of rHSA/IFNα2a or 180 μg of PEG-IFNα2a for 3 months. Tolerability, pharmacokinetics and antiviral responses were assessed., Results: Thirty-one of 32 enrolled patients completed the treatment study. The rHSA/IFNα2a treatment was better tolerated than the PEG-IFNα2a 180 μg treatment, as evidenced by blood cell counts and higher serum albumin levels. Half-life (t 1/2 ) of rHSA/IFNα2a was estimated to be 120-140 h, and is potentially suitable for a dosing interval of 2 weeks or longer. Pharmacokinetics of the last dose between rHSA/IFNα2a 750 μg and PEG-IFNα2a 180 μg, with the exception of t 1/2 , was comparable, and a similar kinetics of inhibiting HBV DNA replication was observed in both groups. Mean reductions in serum HBV DNA levels after treatment were -1.32, -2.13, -1.10 and -2.48 log10 IU/ml in the 600, 750 and 900 μg rHSA/IFNα2a groups and PEG-IFNα2a group, respectively., Conclusions: The rHSA/IFNα2a treatment was well tolerated and can be administered biweekly. Similar efficacy in inhibiting HBV replication was observed in both PEG-IFNα2a and rHSA/IFNα2a 750 μg groups., (© 2016 The British Pharmacological Society.)

Background: A new, potent, long lasting recombinant interferon variant (pegylated consensus interferon, PEGCIFN) was expressed by Escherichia coli. The aim of this study was to test safety and antiviral activity of the new type of interferon in adults with hepatitis C virus (HCV) infection and to determine the relationship between immune response markers and virological response., Method: 40 naive HCV patients (1 : 1 : 1 : 1) were injected subcutaneously with PEG-CIFN 1.0, 1.5, 2.0 μg/kg and peginterferon-α 180 μg once per week for 12 weeks. Serum HCV RNA, cytokines, chemokines levels were tested, and clinical data were collected at this course., Results: PEG-CIFN is safety/tolerability. The serum HCV RNA levels were markedly decreased after therapy. 20% (2/10), 70% (7/10), 70% (7/10), and 60% (6/10) exhibited early virologic responses (EVR (+)) during PEGCIFN 1.0, 1.5, and 2.0 μg/kg treatment and peginterferon-α 180 μg treatment, respectively. Interleukin-4, interferon induced protein 10 (IP-10), and macrophage inflammatory protein 1β (MIP-1β) levels were lower, and granulocyte colony-stimulating factor levels were higher in EVR (+) than in the group not having an EVR (EVR (-)) (p < 0.05) after PEG-CIFN treatment. IP-10 and MIP-1β levels were associated with HCV RNA values, alanine aminotransferase, and aspartate aminotransferase levels after PEG-CIFN treatment., Conclusion: PEGCIFN was well tolerated and effective at inhibiting HCV RNA, which is associated with changes in markers of immune response. PEG-CIFN 1.5 μg/kg has been selected for further hepatitis C clinical development.

To synthesise and characterize the polyoxometalate Cs(2)K(4)Na[SiW(9)Nb(3)O(40)]·H(2)O 1 for its anti-hepatitis B virus (HBV) properties by using the HepG2.2.15 cell. The methylthiazol tetrazolium assay was used to evaluate the growth inhibitory effect of Compound 1 on HepG2.2.15 cell. By using ELISA and real-time PCR, respectively, the presence of extracellular hepatitis B surface antigen (HBsAg), e antigen (HBeAg), and HBV DNA were measured. The levels of intracellular HBV DNA and mRNA were determined by using Southern blot or reverse-transcription-PCR, respectively. Intracellular distribution of antigen were measured by Western blot. A 1995 μmol/L concentration of the commercially-available hepatitis B drug, adefovir dipivoxil (ADV), was required to achieve 50% cytotoxicity against cultured cells (CC(50)) by day nine; in contrast, only 1747 μmol/L of Compound 1 was required for the same result. Treatment of HepG2.2.15 cells with Compound 1 effectively suppress the secretion of HBV antigens and HBV DNA in a dose-dependent and time-dependent manner. IC(50) values were determined to be 80 μmol/L for HBsAg, 75 μmol/L for HBeAg and 3.72 μmol/L for supernatant HBV DNA at day nine post-exposure, as opposed to 266, 296, 30.09 μmol/L, respectively, for ADV. Intracellular HBV DNA, mRNA and antigen were also found to be decreased by Compound 1. The same dose of ADV yielded a significantly less robust inhibitory effect. Compound 1 can clear HBV from hepatic cells and may represent a therapeutic agent to treat HBV infection., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Highlights: [•] Grass carp TRIF exhibits sequence divergence from its orthologs. [•] CiTRIF might activate IFN in distinct manner from that in mammals. [•] CiTRIF plays a critical role in RLR pathway in antiviral immune response. [•] CiTRIF inhibits GCRV replication in CIK cells. [ABSTRACT FROM AUTHOR]

Highlights: [•] Two HMGB2 co-ortholog genes were identified and characterized from grass carp. [•] CiHMGB2a/2b widely express in different tissues. [•] CiHMGB2a/2b involve in immune responses to dsRNA virus and viral/bacterial PAMPs. [•] CiHMGB2a/2b participate in the classical antiviral immune pathways. [•] CiHMGB2a/2b facilitate each other and exhibit strong antiviral activity. [ABSTRACT FROM AUTHOR]