scholarly journals Synthesis of some benzimidazole derivatives endowed with 1,2,3-triazole as potential inhibitors of hepatitis C virus

2016 ◽  
Vol 66 (2) ◽  
pp. 219-231 ◽  
Author(s):  
Bahaa G. M. Youssif ◽  
Yaseen A. M. Mohamed ◽  
Mohammed T. A. Salim ◽  
Fuyuhiko Inagaki ◽  
Chisato Mukai ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Viable Cell ◽  
Benzimidazole Derivatives ◽  
Significant Activity ◽  
B Virus ◽  
Potential Inhibitors ◽  
Derivatives Of ◽  
Insight Into

Abstract New derivatives of 2-thiobenzimidazole incorporating triazole moiety were synthesized, characterized and tested in vitro for antiviral activity against hepatitis C virus (HCV) and hepatitis B virus (HBV). Their cytotoxicity was determined by the reduction in the number of viable cell. All of the synthesized compounds are inactive against HBV and some showed activity against HCV. In particular, two compounds showed significant activity, 2-{4-[(1-benzoylbenzimidazol-2-ylthio)methyl]-1H-1,2,3-triazol-1-yl}-N-(p-nitro-phenyl)-acetamide (13) and 2-(4-{[1-(p-chlorobenzoyl)-benzimidazol-2-ylthio)methyl]-1H-1,2,3-triazol-1-yl}-N-(p-nitrophenyl)-acetamide (17). The results give an insight into the importance of the substituent at position 2 of benzimidazole for the inhibition of HCV.

scholarly journals The Octadecyloxyethyl Ester of (S)-9-[3-Hydroxy-2-(Phosphonomethoxy) Propyl]Adenine Is a Potent and Selective Inhibitor of Hepatitis C Virus Replication in Genotype 1A, 1B, and 2A Replicons

2009 ◽  
Vol 53 (6) ◽  
pp. 2660-2662 ◽  
Author(s):  
David L. Wyles ◽  
Kelly A. Kaihara ◽  
Brent E. Korba ◽  
Robert T. Schooley ◽  
James R. Beadle ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Virus Replication ◽  
Active Compound ◽  
Hcv Rna ◽  
Genotype 1A ◽  
B Virus ◽  
Immunodeficiency Virus

ABSTRACT The octadecyloxyethyl (ODE) and hexadecyloxypropyl (HDP) esters of (S)-9-[3-hydroxy-2-(phosphonomethoxy)propyl]adenine (HPMPA) are potent inhibitors of orthopoxvirus, herpesvirus, human immunodeficiency virus type 1, and hepatitis B virus replication in vitro. HDP and ODE esters of (S)-HPMPA and (R)-HPMPA were evaluated for their activity in hepatitis C virus (HCV) replicon assays using luciferase (1B and 2A replicons) or RNA (1B) quantification. The ODE ester of (S)-HPMPA [ODE-(S)-HPMPA] was the most active compound, with 50% effective concentrations (EC50s) in the 0.69 to 1.31 μM range. HDP and ODE esters of (R)-HPMPA were severalfold less active, while (S)-HPMPA and (R)-HPMPA were inactive. In genotype 1A and 1B replicons analyzed by HCV RNA analysis, ODE-(S)-HPMPA was the most active compound, with EC50s of 1.8 and 2.1 μM, respectively.

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 In Vitro RNA Replication Directed by Replicase Complexes Isolated from the Subgenomic Replicon Cells of Hepatitis C Virus

2003 ◽  
Vol 77 (3) ◽  
pp. 2295-2300 ◽  
Author(s):  
Vicky C. H. Lai ◽  
Shannon Dempsey ◽  
Johnson Y. N. Lau ◽  
Zhi Hong ◽  
Weidong Zhong
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Rna Synthesis ◽  
Divalent Cations ◽  
Hcv Rna ◽  
Nonstructural Proteins ◽  
Subgenomic Replicon ◽  
Free System ◽  
Potential Inhibitors

ABSTRACT Replication of hepatitis C virus (HCV) RNA in virus-infected cells is believed to be catalyzed by viral replicase complexes (RCs), which may consist of various virally encoded nonstructural proteins and host factors. In this study, we characterized the RC activity of a crude membrane fraction isolated from HCV subgenomic replicon cells. The RC preparation was able to use endogenous replicon RNA as a template to synthesize both single-stranded (ss) and double-stranded (ds) RNA products. Divalent cations (Mg2+ and Mn2+) showed different effects on RNA synthesis. Mg2+ ions stimulated the synthesis of ss RNA but had little effect on the synthesis of ds RNA. In contrast, Mn2+ ions enhanced primarily the synthesis of ds RNA. Interestingly, ss RNA could be synthesized under certain conditions in the absence of ds RNA, and vice versa, suggesting that the ss and ds RNA were derived either from different forms of replicative intermediates or from different RCs. Pulse-chase analysis showed that radioactivity incorporated into the ss RNA was chased into the ds RNA and other larger RNA species. This observation indicated that the newly synthesized ss RNA could serve as a template for a further round of RNA synthesis. Finally, 3′ deoxyribonucleoside triphosphates were able to inhibit RNA synthesis in this cell-free system, presumably through chain termination, with 3′ dGTP having the highest potency. Establishment of the replicase assay will facilitate the identification and evaluation of potential inhibitors that would act against the entire RC of HCV.

scholarly journals Inhibition of Hepatitis C Virus Replicon RNA Synthesis by PSI-352938, a Cyclic Phosphate Prodrug of β-d-2′-Deoxy-2′-α-Fluoro-2′-β-C-Methylguanosine

2011 ◽  
Vol 55 (6) ◽  
pp. 2566-2575 ◽  
Author(s):  
Angela M. Lam ◽  
Christine Espiritu ◽  
Eisuke Murakami ◽  
Veronique Zennou ◽  
Shalini Bansal ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Cross Resistance ◽  
Content Type ◽  
Dna And Rna ◽  
Genotype 1A ◽  
B Virus ◽  
Cyclic Phosphate ◽  
Nonnucleoside Inhibitors

ABSTRACTPSI-352938 is a novel cyclic phosphate prodrug of β-d-2′-deoxy-2′-α-fluoro-2′-β-C-methylguanosine 5′-monophosphate that has potent activity against hepatitis C virus (HCV)in vitro. The studies described here characterize thein vitroanti-HCV activity of PSI-352938, alone and in combination with other inhibitors of HCV, and the cross-resistance profile of PSI-352938. The effective concentration required to achieve 50% inhibition for PSI-352938, determined using genotype 1a-, 1b-, and 2a-derived replicons stably expressed in the Lunet cell line, were 0.20, 0.13, and 0.14 μM, respectively. The active 5′-triphosphate metabolite, PSI-352666, inhibited recombinant NS5B polymerase from genotypes 1 to 4 with comparable 50% inhibitory concentrations. In contrast, PSI-352938 did not inhibit the replication of hepatitis B virus or human immunodeficiency virusin vitro. PSI-352666 did not significantly affect the activity of human DNA and RNA polymerases. PSI-352938 and its cyclic phosphate metabolites did not affect the cyclic GMP-mediated activation of protein kinase G. Clearance studies using replicon cells demonstrated that PSI-352938 cleared cells of HCV replicon RNA and prevented replicon rebound. An additive to synergistic effect was observed when PSI-352938 was combined with other classes of HCV inhibitors, including alpha interferon, ribavirin, NS3/4A inhibitors, an NS5A inhibitor, and nucleoside/nucleotide and nonnucleoside inhibitors. Cross-resistance studies showed that PSI-352938 remained fully active against replicons containing the S282T or the S96T/N142T amino acid alteration. Replicons that contain mutations conferring resistance to various classes of nonnucleoside inhibitors also remained sensitive to inhibition by PSI-352938. PSI-352938 is currently being evaluated in a phase I clinical study in genotype 1-infected individuals.

scholarly journals Synthesis and Anti-Hepatitis B Virus and Anti-Hepatitis C Virus Activities of 7-Deazaneplanocin A Analogues in Vitro

2009 ◽  
Vol 52 (1) ◽  
pp. 206-213 ◽  
Author(s):  
Hyo-Joong Kim ◽  
Ashoke Sharon ◽  
Chandralata Bal ◽  
Jianing Wang ◽  
Madhan Allu ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Hepatitis B Virus ◽  
Hepatitis B ◽  
B Virus

Alkoholabstinenz allein verbessert die Leberfunktion und verlängert das Überleben bei der alkoholischen Lebererkrankung!

2016 ◽  
Vol 62 (6) ◽  
pp. 396-400 ◽  
Author(s):  
Helmut K. Seitz ◽  
Tatjana Arslic-Schmitt
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Hepatitis B Virus ◽  
Hepatitis B ◽  
B Virus ◽  
Alkoholische Lebererkrankung ◽  
Alkoholische Steatohepatitis

Zusammenfassung. Zielsetzung: Im Folgenden soll dargelegt werden, dass Alkoholkarenz sowohl die Leberfunktion als auch das Überleben in jedem Stadium einer alkoholischen Lebererkrankung günstig beeinflusst. Ergebnisse: Täglicher Alkoholkonsum von mehr als 25 Gramm reinen Alkohols, etwas mehr als ¼ Liter Wein beim Mann und etwa die Hälfte bei der Frau sind, mit einem erhöhten Risiko für eine alkoholische Lebererkrankung (ALE) behaftet. Die ALE besteht aus einem breiten Spektrum von histopathologischen Veränderungen. Sie beginnt immer mit einer alkoholischen Fettleber, die sich in eine alkoholische Steatohepatitis weiterentwickeln kann. Fortgeschrittene Formen der ALE beinhalten die Leberfibrose, die Leberzirrhose und das hepatozelluläre Karzinom. In der Behandlung jeder Form der ALE ist die Alkoholabstinenz von zentraler Bedeutung. Ein Großteil der alkoholischen Fettlebern bildet sich unter Alkoholkarenz oder sogar Alkoholreduktion zurück. Die alkoholische Hepatitis, ein klinisches Syndrom mit hoher Mortalität, führt ohne Alkoholkarenz innerhalb von Tagen und Wochen zum Tode. Darüber hinaus ist selbst die Leberfibrose (perivenös und perisinusoidal) unter Alkoholkarenz rückbildungsfähig. Bei allen Formen der fortgeschrittenen ALE (kompensiert und nicht-kompensierte Leberzirrhose) wird die Mortalität durch Alkoholkarenz oder signifikante Reduktion im Gegensatz zum fortgesetzten Alkoholkonsum signifikant verringert. Selbst Patienten mit alkoholischer Leberzirrhose können über mehr als 20 Jahre ohne Komplikationen weiterleben, wenn sie komplett auf Alkohol verzichten. Schlussfolgerung: Im Vergleich zu Leberzirrhose anderer Ätiologie, wie zum Beispiel Zirrhosen, die durch das Hepatitis-B Virus oder das Hepatitis-C Virus verursacht sind, haben alkoholische Leberzirrhosen unter Alkoholkarenz eine wesentlich bessere Prognose. Damit ist Alkoholkarenz eine gute Therapie und der Erfolg jeder anderen neuen Therapie muss mit Alkoholkarenz verglichen werden.

Funktion von CEACAM-1 im Rahmen der Therapie der Hepatitis C-Virus Infektion mit Interferon-alpha in vivo und in vitro

2006 ◽  
Vol 44 (08) ◽  
Author(s):  
P Hilgard ◽  
R Bröring ◽  
M Trippler ◽  
S Viazov ◽  
G Gerken ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Interferon Alpha
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