scholarly journals In Vitro Antiviral Activity of Tyrosinase from Mushroom Agaricus bisporus against Hepatitis C Virus

2021 ◽  
Vol 14 (8) ◽  
pp. 759
Author(s):  
David Lopez-Tejedor ◽  
Rafael Claveria-Gimeno ◽  
Adrian Velazquez-Campoy ◽  
Olga Abian ◽  
Jose M. Palomo
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Antiviral Activity ◽  
Agaricus Bisporus ◽  
Catalytic Mechanism ◽  
Inhibition Mechanism ◽  
Viral Proteases ◽  
Inactive Form ◽  
Hepatitis C Virus Proteins

Tyrosinases from a commercial Agaricus bisporus protein extract and directly isolated from white mushrooms were purified in order to obtaining the well-known tyrosinase from A. bisporus (TyrAB) of 45 kDa and a newly discovered 50 kDa tyrosinase isoform (Tyr50 kDa), and tested showing high antiviral activity against the hepatitis C virus for the first time. Cell toxicity and antiviral activity of tyrosinases were determined in cultured Huh 5-2 liver tumor cells transfected with a replicon system (a plasmid that includes all non-structural hepatitis C virus proteins and replicates autonomously). TyrAB was able to inhibit the replication of the hepatitis C virus without inducing toxicity in liver cells. In addition, the post-translational isoform Tyr50 kDa showed higher antiviral capacity than the former (up to 10 times greater), also exhibiting 10 times higher activity than the commercial drug Ribavirin®. This antiviral activity was directly proportional to the enzymatic activity of tyrosinases, as no antiviral capacity was observed in the inactive form of the enzymes. The tyrosinases approach could represent a new antiviral inhibition mechanism, through a plausible catalytic mechanism of selective hydroxylation of the key role of tyrosine residues in viral proteases.

scholarly journals Tyrosinase from mushroom Agaricus bisporus as an inhibitor of the Hepatitis C virus

2020 ◽  
Author(s):  
David Lopez-Tejedor ◽  
Rafael Clavería-Gimeno ◽  
Adrian Velazquez-Campoy ◽  
Olga Abian ◽  
Jose M. Palomo
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Antiviral Activity ◽  
Agaricus Bisporus ◽  
Catalytic Mechanism ◽  
Low Cost ◽  
Inhibition Mechanism ◽  
System A ◽  
Viral Proteases ◽  
Hepatitis C Virus Proteins

AbstractTyrosinases from both a commercial semi-purified Agaricus bisporus protein extract and directly isolated from white mushroom have been demonstrated to show antiviral activity against the Hepatitis C virus for the first time. The well-known tyrosinase from A. bisporus (TyrAB) of 45kDa and a newly discovered 50-kDa isoform from this tyrosinase (Tyr50kDa) have been tested. Cell toxicity and antiviral activity of tyrosinases in cultured Huh 5-2 liver tumor cells transfected with a replicon system (a plasmid that includes all non-structural Hepatitis C virus proteins and replicates autonomously) was determined. Native TyrAB was able to inhibit the replication of the hepatitis C virus without inducing toxicity in liver cells. In addition, the post-translational isoform of Tyr50kDa showed higher antiviral capacity than the former (up to 10 times greater), , also exhibiting 10 times higher activity than the commercial drug Ribavirin®. This antiviral activity was directly proportional to the enzymatic activity of tyrosinases, since no antiviral capacity was observed for the inactive enzymes. The tyrosinases could represent a new antiviral inhibition mechanism through a catalytic mechanism of selective hydroxylation of key role tyrosine residues in viral proteases. The tyrosinases directly extracted from fresh mushroom (containing both tyrosinases) showed similar antiviral activity and, therefore, might provide low-cost drugs for the treatment of hepatitis C.

scholarly journals Comparison of Daclatasvir Resistance Barriers on NS5A from Hepatitis C Virus Genotypes 1 to 6: Implications for Cross-Genotype Activity

2014 ◽  
Vol 58 (9) ◽  
pp. 5155-5163 ◽  
Author(s):  
Chunfu Wang ◽  
Lingling Jia ◽  
Donald R. O'Boyle ◽  
Jin-Hua Sun ◽  
Karen Rigat ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Antiviral Activity ◽  
Rank Order ◽  
Replicon Cell ◽  
Hcv Genotypes ◽  
Resistance Selection ◽  
Virus Genotypes ◽  
Hepatitis C Virus Genotypes

ABSTRACTA comparison of the daclatasvir (DCV [BMS-790052]) resistance barrier on authentic or hybrid replicons containing NS5A from hepatitis C virus (HCV) genotypes 1 to 6 (GT-1 to -6) was completed using a replicon elimination assay. The data indicated that genotype 1b (GT-1b) has the highest relative resistance barrier and genotype 2a (GT-2a M31) has the lowest. The rank order of resistance barriers to DCV was 1b > 4a ≥ 5a > 6a ≅ 1a > 2a JFH > 3a > 2a M31. Importantly, DCV in combination with a protease inhibitor (PI) eliminated GT-2a M31 replicon RNA at a clinically relevant concentration. Previously, we reported the antiviral activity and resistance profiles of DCV on HCV genotypes 1 to 4 evaluated in the replicon system. Here, we report the antiviral activity and resistance profiles of DCV against hybrid replicons with NS5A sequences derived from HCV GT-5a and GT-6a clinical isolates. DCV was effective against both GT-5a and -6a hybrid replicon cell lines (50% effective concentrations [EC50s] ranging from 3 to 7 pM for GT-5a, and 74 pM for GT-6a). Resistance selection identified amino acid substitutions in the N-terminal domain of NS5A. For GT-5a, L31F and L31V, alone or in combination with K56R, were the major resistance variants (EC50s ranging from 2 to 40 nM). In GT-6a, Q24H, L31M, P32L/S, and T58A/S were identified as resistance variants (EC50s ranging from 2 to 250 nM). Thein vitrodata suggest that DCV has the potential to be an effective agent for HCV genotypes 1 to 6 when used in combination therapy.

scholarly journals Preclinical Characterization of the Novel Hepatitis C Virus NS3 Protease Inhibitor GS-9451

2013 ◽  
Vol 58 (2) ◽  
pp. 647-653 ◽  
Author(s):  
Huiling Yang ◽  
Margaret Robinson ◽  
Amoreena C. Corsa ◽  
Betty Peng ◽  
Guofeng Cheng ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Antiviral Activity ◽  
Protease Inhibitor ◽  
Hcv Infection ◽  
Cross Resistance ◽  
Protease Gene ◽  
Ns5a Inhibitor ◽  
Ns3 Protease

ABSTRACTGS-9451 is a selective hepatitis C virus (HCV) NS3 protease inhibitor in development for the treatment of genotype 1 (GT1) HCV infection. Key preclinical properties of GS-9451, includingin vitroantiviral activity, selectivity, cross-resistance, and combination activity, as well as pharmacokinetic properties, were determined. In multiple GT1a and GT1b replicon cell lines, GS-9451 had mean 50% effective concentrations (EC50s) of 13 and 5.4 nM, respectively, with minimal cytotoxicity; similar potency was observed in chimeric replicons encoding the NS3 protease gene of GT1 clinical isolates. GS-9451 was less active in GT2a replicon cells (EC50= 316 nM). Additive to synergisticin vitroantiviral activity was observed when GS-9451 was combined with other agents, including alpha interferon, ribavirin, and the polymerase inhibitors GS-6620 and tegobuvir (GS-9190), as well as the NS5A inhibitor ledipasvir (GS-5885). GS-9451 retained wild-type activity against multiple classes of NS5B and NS5A inhibitor resistance mutations. GS-9451 was stable in hepatic microsomes and hepatocytes from human and three other tested species. Systemic clearance was low in dogs and monkeys but high in rats. GS-9451 showed good oral bioavailability in all three species tested. In rats, GS-9451 levels were ∼40-fold higher in liver than plasma after intravenous dosing, and elimination of GS-9451 was primarily through biliary excretion. Together, these results are consistent with the antiviral activity observed in a recent phase 1b study. The results ofin vitrocross-resistance and combination antiviral assays support the ongoing development of GS-9451 in combination with other agents for the treatment of chronic HCV infection.

scholarly journals Ribavirin Antagonizes the In Vitro Anti-Hepatitis C Virus Activity of 2′-C-Methylcytidine, the Active Component of Valopicitabine

2006 ◽  
Vol 50 (10) ◽  
pp. 3444-3446 ◽  
Author(s):  
Lotte Coelmont ◽  
Jan Paeshuyse ◽  
Marc P. Windisch ◽  
Erik De Clercq ◽  
Ralf Bartenschlager ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Antiviral Activity ◽  
Protease Inhibitor ◽  
Nucleoside Analogue ◽  
Active Component ◽  
Pyrimidine Nucleoside ◽  
Virus Activity ◽  
Hcv Protease

ABSTRACT Ribavirin antagonizes the in vitro anti-hepatitis C virus (HCV) activity of the pyrimidine nucleoside analogue 2′-C-methylcytidine, the active component of the experimental anti-HCV drug valopicitabine. In contrast, the combination of ribavirin with either the purine nucleoside analogue 2′-C-methyladenosine or the HCV protease inhibitor VX-950 resulted in an additive antiviral activity. These findings may have implications when planning clinical studies with valopicitabine.

scholarly journals In VitroAntiviral Activity and Resistance Profile Characterization of the Hepatitis C Virus NS5A Inhibitor Ledipasvir

2016 ◽  
Vol 60 (3) ◽  
pp. 1847-1853 ◽  
Author(s):  
Guofeng Cheng ◽  
Yang Tian ◽  
Brian Doehle ◽  
Betty Peng ◽  
Amoreena Corsa ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Antiviral Activity ◽  
Fixed Dose ◽  
Resistance Profile ◽  
Direct Acting Antiviral ◽  
Ns5b Polymerase Inhibitor ◽  
Polymerase Inhibitor ◽  
Ns5b Polymerase

Ledipasvir (LDV; GS-5885), a component of Harvoni (a fixed-dose combination of LDV with sofosbuvir [SOF]), is approved to treat chronic hepatitis C virus (HCV) infection. Here, we report key preclinical antiviral properties of LDV, includingin vitropotency,in vitroresistance profile, and activity in combination with other anti-HCV agents. LDV has picomolar antiviral activity against genotype 1a and genotype 1b replicons with 50% effective concentration (EC50) values of 0.031 nM and 0.004 nM, respectively. LDV is also active against HCV genotypes 4a, 4d, 5a, and 6a with EC50values of 0.11 to 1.1 nM. LDV has relatively lessin vitroantiviral activity against genotypes 2a, 2b, 3a, and 6e, with EC50values of 16 to 530 nM.In vitroresistance selection with LDV identified the single Y93H and Q30E resistance-associated variants (RAVs) in the NS5A gene; these RAVs were also observed in patients after a 3-day monotherapy treatment.In vitroantiviral combination studies indicate that LDV has additive to moderately synergistic antiviral activity when combined with other classes of HCV direct-acting antiviral (DAA) agents, including NS3/4A protease inhibitors and the nucleotide NS5B polymerase inhibitor SOF. Furthermore, LDV is active against known NS3 protease and NS5B polymerase inhibitor RAVs with EC50values equivalent to those for the wild type.

861 THE LECTIN GRIFFITHSIN HAS ANTIVIRAL ACTIVITY AGAINST HEPATITIS C VIRUS IN VITRO AND IN VIVO

2012 ◽  
Vol 56 ◽  
pp. S335-S336
Author(s):  
P. Meuleman ◽  
A. Albecka ◽  
S. Belouzard ◽  
K. Vercauteren ◽  
L. Verhoye ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Antiviral Activity

Potent antiviral activity of Solanum rantonnetii and the isolated compounds against hepatitis C virus in vitro

2014 ◽  
Vol 11 ◽  
pp. 185-191 ◽  
Author(s):  
Khaled Rashed ◽  
Marie-Emmanuelle Sahuc ◽  
Gaspard Deloison ◽  
Noémie Calland ◽  
Priscille Brodin ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Antiviral Activity ◽  
Potent Antiviral Activity

scholarly journals PSI-7851, a Pronucleotide of β-d-2′-Deoxy-2′-Fluoro-2′-C-Methyluridine Monophosphate, Is a Potent and Pan-Genotype Inhibitor of Hepatitis C Virus Replication

2010 ◽  
Vol 54 (8) ◽  
pp. 3187-3196 ◽  
Author(s):  
Angela M. Lam ◽  
Eisuke Murakami ◽  
Christine Espiritu ◽  
Holly M. Micolochick Steuer ◽  
Congrong Niu ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Antiviral Activity ◽  
Nucleoside Analogs ◽  
Cross Resistance ◽  
Bone Marrow Toxicity ◽  
Significant Activity ◽  
Dna And Rna ◽  
Highly Active

ABSTRACT The hepatitis C virus (HCV) NS5B RNA polymerase facilitates the RNA synthesis step during the HCV replication cycle. Nucleoside analogs targeting the NS5B provide an attractive approach to treating HCV infections because of their high barrier to resistance and pan-genotype activity. PSI-7851, a pronucleotide of β-d-2′-deoxy-2′-fluoro-2′-C-methyluridine-5′-monophosphate, is a highly active nucleotide analog inhibitor of HCV for which a phase 1b multiple ascending dose study of genotype 1-infected individuals was recently completed (M. Rodriguez-Torres, E. Lawitz, S. Flach, J. M. Denning, E. Albanis, W. T. Symonds, and M. M. Berry, Abstr. 60th Annu. Meet. Am. Assoc. Study Liver Dis., abstr. LB17, 2009). The studies described here characterize the in vitro antiviral activity and cytotoxicity profile of PSI-7851. The 50% effective concentration for PSI-7851 against the genotype 1b replicon was determined to be 0.075 ± 0.050 μM (mean ± standard deviation). PSI-7851 was similarly effective against replicons derived from genotypes 1a, 1b, and 2a and the genotype 1a and 2a infectious virus systems. The active triphosphate, PSI-7409, inhibited recombinant NS5B polymerases from genotypes 1 to 4 with comparable 50% inhibitory concentrations. PSI-7851 is a specific HCV inhibitor, as it lacks antiviral activity against other closely related and unrelated viruses. PSI-7409 also lacked any significant activity against cellular DNA and RNA polymerases. No cytotoxicity, mitochondrial toxicity, or bone marrow toxicity was associated with PSI-7851 at the highest concentration tested (100 μM). Cross-resistance studies using replicon mutants conferring resistance to modified nucleoside analogs showed that PSI-7851 was less active against the S282T replicon mutant, whereas cells expressing a replicon containing the S96T/N142T mutation remained fully susceptible to PSI-7851. Clearance studies using replicon cells demonstrated that PSI-7851 was able to clear cells of HCV replicon RNA and prevent viral rebound.

scholarly journals SCY-635, a Novel Nonimmunosuppressive Analog of Cyclosporine That Exhibits Potent Inhibition of Hepatitis C Virus RNA Replication In Vitro

2009 ◽  
Vol 54 (2) ◽  
pp. 660-672 ◽  
Author(s):  
Sam Hopkins ◽  
Bernard Scorneaux ◽  
Zhuhui Huang ◽  
Michael G. Murray ◽  
Stephen Wring ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Antiviral Activity ◽  
Mononuclear Cells ◽  
Human Peripheral Blood ◽  
Interleukin 2 ◽  
Jurkat Cells ◽  
Cytochrome P450 Enzymes ◽  
Peripheral Blood Mononuclear

ABSTRACT SCY-635 is a novel nonimmunosuppressive cyclosporine-based analog that exhibits potent suppression of hepatitis C virus (HCV) replication in vitro. SCY-635 inhibited the peptidyl prolyl isomerase activity of cyclophilin A at nanomolar concentrations but showed no detectable inhibition of calcineurin phosphatase activity at concentrations up to 2 μM. Metabolic studies indicated that SCY-635 did not induce the major cytochrome P450 enzymes 1A2, 2B6, and 3A4. SCY-635 was a weak inhibitor and a poor substrate for P-glycoprotein. Functional assays with stimulated Jurkat cells and stimulated human peripheral blood mononuclear cells indicated that SCY-635 is a weaker inhibitor of interleukin-2 secretion than cyclosporine. A series of two-drug combination studies was performed in vitro. SCY-635 exhibited synergistic antiviral activity with alpha interferon 2b and additive antiviral activity with ribavirin. SCY-635 was shown to be orally bioavailable in multiple animal species and produced blood and liver concentrations of parent drug that exceeded the 50% effective dose determined in the bicistronic con1b-derived replicon assay. These results suggest that SCY-635 warrants further investigation as a novel therapeutic agent for the treatment of individuals who are chronically infected with HCV.

Sign in / Sign up

Export Citation Format

Share Document