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HCV nonstructural

Astrid M Newsum, Cynthia K Y Ho, Faydra I Lieveld, Thijs J W van de Laar, Sylvie M Koekkoek, Sjoerd P Rebers, Jan T M van der Meer, Anne M J Wensing, Greet J Boland, Joop E Arends, Karel J van Erpecum, Maria Prins, Richard Molenkamp, Janke Schinkel
OBJECTIVES: The Q80K polymorphism is a naturally occurring resistance-associated variant in the hepatitis C virus (HCV) nonstructural protein 3 (NS3) region and is likely transmissible between hosts. This study describes the Q80K origin and prevalence among HCV risk groups in the Netherlands and examines whether Q80K is linked to specific transmission networks. DESIGN AND METHODS: Stored blood samples from HCV genotype 1a-infected patients were used for PCR and sequencing to reconstruct the NS3 maximum likelihood phylogeny...
January 2, 2017: AIDS
Ling Tong, Wensheng Yu, Lei Chen, Oleg Selyutin, Michael P Dwyer, Anilkumar Gopinadhan Nair, Robert Mazzola, Jae-Hun Kim, Deyou Sha, Jingjun Yin, Rebecca Tamra Ruck, Ian W Davies, Bin Hu, Bin Zhong, Jinglai Hao, Tao Ji, Shuai Zan, Rong Liu, Sony Agrawal, Ellen Xia, Stephanie Curry, Patricia Mcmonagle, Karin Bystol, Frederick Lahser, Donna Carr, Laura Rokosz, Paul Ingravallo, Shiying Chen, Kung-I Feng, Mark Cartwright, Ernest Asante-Appiah, Joseph A Kozlowski
We describe the research that led to the discovery of compound 40 (ruzasvir, MK-8408), a pan-genotypic HCV nonstructural protein 5A (NS5A) inhibitor with a "flat" GT1 mutant profile. This NS5A inhibitor contains a unique tetracyclic indole core, while maintaining the imidazole-proline-valine Moc motifs of our previous NS5A inhibitors. Compound 40 is currently in early clinical trials and is under evaluation as part of an all-oral DAA regimen for the treatment of chronic HCV infection..
November 3, 2016: Journal of Medicinal Chemistry
Rina Barouch-Bentov, Gregory Neveu, Fei Xiao, Melanie Beer, Elena Bekerman, Stanford Schor, Joseph Campbell, Jim Boonyaratanakornkit, Brett Lindenbach, Albert Lu, Yves Jacob, Shirit Einav
: Enveloped viruses commonly utilize late-domain motifs, sometimes cooperatively with ubiquitin, to hijack the endosomal sorting complex required for transport (ESCRT) machinery for budding at the plasma membrane. However, the mechanisms underlying budding of viruses lacking defined late-domain motifs and budding into intracellular compartments are poorly characterized. Here, we map a network of hepatitis C virus (HCV) protein interactions with the ESCRT machinery using a mammalian-cell-based protein interaction screen and reveal nine novel interactions...
November 1, 2016: MBio
Tushar Garimella, Xiaoli You, Reena Wang, Shu-Pang Huang, Hamza Kandoussi, Marc Bifano, Richard Bertz, Timothy Eley
: The treatment of hepatitis C virus (HCV) infection has been revolutionized in recent years by the development of direct-acting antiviral regimens that do not contain peginterferon (pegIFN) and/or ribavirin (RBV). While direct-acting antiviral-based regimens have been shown to be greatly superior to pegIFN/RBV-based regimens in terms of efficacy and safety, they have a greater susceptibility to drug-drug interactions (DDIs). Daclatasvir (DCV)-the benchmark pangenotypic nonstructural protein 5A inhibitor-has been shown to be efficacious and generally well tolerated in partnership with other HCV direct-acting antivirals, including sofosbuvir, asunaprevir (ASV), and ASV plus beclabuvir...
November 2016: Advances in Therapy
Ling Tong, Wensheng Yu, Craig A Coburn, Peter T Meinke, Anilkumar G Nair, Michael P Dwyer, Lei Chen, Oleg Selyutin, Stuart B Rosenblum, Yueheng Jiang, James Fells, Bin Hu, Bin Zhong, Richard M Soll, Rong Liu, Sony Agrawal, Ellen Xia, Ying Zhai, Rong Kong, Paul Ingravallo, Amin Nomeir, Ernest Asante-Appiah, Joseph A Kozlowski
Herein, we describe our research efforts to develop unique cores in molecules which function as HCV nonstructural protein 5A (NS5A) inhibitors. In particular, various fused tetracyclic cores were identified which showed genotype and mutant activities comparable to the indole-based tetracyclic core.
October 15, 2016: Bioorganic & Medicinal Chemistry Letters
Xiaoqiong Shao, Qiumin Luo, Qingxian Cai, Fulong Zhang, Jiangyun Zhu, Ying Liu, Zhixin Zhao, Zhiliang Gao, Xiaohong Zhang
An outbreak of hepatitis C virus (HCV) infections, for which the risk factor was unknown, was previously identified in North Guangdong, China. In the present study, a total of 736 local residents were surveyed regarding their lifetime risk factors for HCV infection. Serum anti‑HCV antibodies and HCV RNA were examined to confirm infection. In the HCV‑positive samples, the core and nonstructural protein 5B sequences were amplified, and phylogenetic analysis was performed to determine the association between HCV subtypes and transmission routes...
September 13, 2016: Molecular Medicine Reports
Wim Schuermans, Hans Orlent, Isabelle Desombere, Patrick Descheemaeker, Hans Van Vlierberghe, Anja Geerts, Xavier Verhelst, Marijke Reynders, Elizaveta Padalko
As different hepatitis C virus (HCV) genotypes respond differently to initiated therapy, correct HCV genotyping is essential. A potential risk for misclassification of the intergenotypic HCV circulating recombinant form (CRF) 2k/1b strains exists, depending on the genotyping method used. The aim was to investigate the differences in HCV genotyping methods with regard to CRF 2k/1b and to gain insight in the prevalence of the CRF 2k/1b. Genotyping results by Versant HCV Genotype Assay were compared with nonstructural protein 5B (NS5B) sequencing...
2016: International Journal of Molecular Sciences
Van T T Huynh, Yun-Sook Lim, Si C Tran, Tu M Pham, Lam N Nguyen, Soon B Hwang
The propagation of hepatitis C virus (HCV) is highly dependent on host cellular factors. To identify the cellular factors involved in HCV propagation, we have previously performed protein microarray assays using the HCV nonstructural 5A (NS5A) protein as a probe. Of ∼9,000 host proteins immobilized in a microarray, ∼90 cellular proteins were identified as HCV NS5A interacting partners. Of these candidates, we selected Abelson interactor 1 (Abi1) for further characterization. Binding of HCV NS5A to Abi1 was verified by both in vitro pulldown and coimmunoprecipitation assays...
October 21, 2016: Journal of Biological Chemistry
Mueed Ur Rahman, Hao Liu, Abdul Wadood, Hai-Feng Chen
HCV RNA dependent RNA polymerase (RdRp) nonstructural protein 5B (NS5B) is a major target against hepatitis C virus (HCV) for antiviral therapy. Recently discovered cyclopropylindolobenzazepine derivatives have been considered as the most potent for their ability to bind the thumb site 1 domain and allosterically inhibit HCV NS5B RdRp activity. However, the allosteric mechanism for these derivatives has not been clarified at the molecular level. In this study, fluctuation correlation networks were constructed based on all-atom molecular dynamics simulations to elucidate the allosteric mechanism...
October 18, 2016: Molecular BioSystems
Abdelfattah M Attallah, Sanaa O Abdallah, Mohamed S Albannan, Mohamed M Omran, Ahmed A Attallah, Khaled Farid
Hepatitis C virus (HCV)/Schistosoma mansoni coinfection is common in Egypt and other developing countries. This study aimed to investigate the influence of HCV/S. mansoni coinfection on the concentration of HCV-nonstructural protein-4 (NS4) in addition to collagen III and matrix metalloproteinase-1 (MMP-1) in different hepatic fibrosis stages. We found that coinfected patients (N = 186) showed significantly (P < 0.05, Mann-Whitney U test) higher concentrations of HCV-NS4, collagen III, and collagen III/MMP-1 ratio (CMR) than those with HCV monoinfection (N = 104) in different fibrosis stages...
November 2, 2016: American Journal of Tropical Medicine and Hygiene
Christopher M Owens, Bradley B Brasher, Alex Polemeropoulos, Michael H J Rhodin, Nicole McAllister, Kelly A Wong, Christopher T Jones, Lijuan Jiang, Kai Lin, Yat Sun Or
EDP-239, a potent and selective hepatitis C virus (HCV) nonstructural protein 5A (NS5A) inhibitor developed for the treatment of HCV infection, has been investigated in vitro and in vivo This study sought to characterize genotypic changes in the HCV NS5A sequence of genotype 1 (GT1) replicons and to compare those changes to GT1 viral RNA mutations isolated from clinical trial patients. Resistance selection experiments in vitro using a subgenomic replicon identified resistance-associated mutations (RAMs) at GT1a NS5A amino acid positions 24, 28, 30, 31, and 93 that confer various degrees of resistance to EDP-239...
October 2016: Antimicrobial Agents and Chemotherapy
Christopher M Owens, Bradley B Brasher, Alex Polemeropoulos, Michael H J Rhodin, Nicole McAllister, Xiaowen Peng, Ce Wang, Lu Ying, Hui Cao, Eric Lawitz, Fred Poordad, Juan Rondon, Terry D Box, Stefan Zeuzem, Peter Buggisch, Kai Lin, Yao-Ling Qiu, Lijuan Jiang, Richard Colvin, Yat Sun Or
EDP-239, a novel hepatitis C virus (HCV) inhibitor targeting nonstructural protein 5A (NS5A), has been investigated in vitro and in vivo EDP-239 is a potent, selective inhibitor with potency at picomolar to nanomolar concentrations against HCV genotypes 1 through 6. In the presence of human serum, the potency of EDP-239 was reduced by less than 4-fold. EDP-239 is additive to synergistic with other direct-acting antivirals (DAAs) or host-targeted antivirals (HTAs) in blocking HCV replication and suppresses the selection of resistance in vitro Furthermore, EDP-239 retains potency against known DAA- or HTA-resistant variants, with half-maximal effective concentrations (EC50s) equivalent to those for the wild type...
October 2016: Antimicrobial Agents and Chemotherapy
Aldo Bonaventura, Fabrizio Montecucco
Hepatitis C virus (HCV) affects 3% of the world population. It represents the main cause of chronic liver disease and is responsible for extra-hepatic complications, such as type 2 diabetes and cardiovascular diseases. HCV includes 7 genotypes differing in the nucleotide sequence variability, the geographic distribution, the rates of viral clearance, the risk of progression to liver fibrosis and to hepatocellular carcinoma, and the response to therapy. Last years have seen remarkable advances in the field of HCV infection with the approval of direct antiviral agents (DAAs) targeting key viral proteins involved in the HCV replication...
July 8, 2016: World Journal of Hepatology
Shaomei Zhu, Tingting Li, Bochao Liu, Yuxia Xu, Yachun Sun, Yilin Wang, Yuanzhan Wang, Lifang Shuai, Zixuan Chen, Jean-Pierre Allain, Chengyao Li
UNLABELLED: A lack of immunocompetent-small-primate models has been an obstacle for developing hepatitis C virus (HCV) vaccines and affordable antiviral drugs. In this study, HCV/GB virus B (GBV-B) chimeric virus carrying the major nonstructural proteins NS2 to NS4A (HCV NS2 to -4A chimera) was produced and used to infect common marmosets, since HCV NS2 to NS4A proteins are critical proteases and major antigens. Seven marmosets were inoculated intrahepatically with HCV NS2 to -4A chimera RNA for primary infection or intravenously injected with chimera-containing serum for passage infection...
September 15, 2016: Journal of Virology
Saverio G Parisi, Arianna Loregian, Samantha Andreis, Giulio Nannetti, Silvia Cavinato, Monica Basso, Renzo Scaggiante, Federico Dal Bello, Lorenzo Messa, Anna Maria Cattelan, Giorgio Palù
OBJECTIVES: Effective treatment with direct-acting antiviral drugs against hepatitis C virus (HCV) is a medical need in cirrhotic HIV-HCV co-infected patients. METHODS: This study investigated the plasma levels of daclatasvir (DCV) and ribavirin (RBV) in HIV-HCV co-infected subjects treated with DCV, sofosbuvir, and RBV. Drug concentrations were quantified using validated high-performance liquid chromatography methods with ultraviolet detection. The HCV non-structural protein 5A and non-structural protein 5B coding regions were analyzed by population-based sequencing...
August 2016: International Journal of Infectious Diseases: IJID
Bo Hu, Shanshan Li, Zhanfeng Zhang, Shenggao Xie, Yuqian Hu, Xianzhang Huang, Yi Zheng
Hepatitis C virus (HCV) nonstructural protein 4B (NS4B) is a multi-transmembrane protein, but little is known about how NS4B contributes to HCV replication and tumorigenesis. Its C-terminal domain (CTD) has been shown to associate with intracellular membrane, and we have previously shown that NS4B CTD contains a class I PDZ-binding motif (PBM). Here, we demonstrated that NS4B PBM interacts with the PDZ-containing tumor suppressor protein, Scribble, using immunofluorescence and co-immunoprecipitation assays, and this interaction requires at least three contiguous PDZ domains of Scribble...
June 17, 2016: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
Cristina M Dorobantu, Lucian Albulescu, Heyrhyoung Lyoo, Mirjam van Kampen, Raffaele De Francesco, Volker Lohmann, Christian Harak, Hilde M van der Schaar, Jeroen R P M Strating, Alexander E Gorbalenya, Frank J M van Kuppeveld
Positive-strand RNA [(+)RNA] viruses are true masters of reprogramming host lipid trafficking and synthesis to support virus genome replication. Via their membrane-associated 3A protein, picornaviruses of the genus Enterovirus (e.g., poliovirus, coxsackievirus, and rhinovirus) subvert Golgi complex-localized phosphatidylinositol 4-kinase IIIβ (PI4KB) to generate "replication organelles" (ROs) enriched in phosphatidylinositol 4-phosphate (PI4P). PI4P lipids serve to accumulate oxysterol-binding protein (OSBP), which subsequently transfers cholesterol to the ROs in a PI4P-dependent manner...
May 2016: MSphere
Tatsuo Kanda, Shin Yasui, Masato Nakamura, Eiichiro Suzuki, Makoto Arai, Yuki Haga, Reina Sasaki, Shuang Wu, Shingo Nakamoto, Fumio Imazeki, Osamu Yokosuka
Background. All-oral combination of direct-acting antivirals could lead to higher sustained virologic response (SVR) in hepatitis C virus (HCV)-infected patients. In the present study, we examined the efficacy and safety of the dual oral treatment with HCV nonstructural protein (NS) 5A inhibitor daclatasvir (DCV) plus HCV NS3/4A inhibitor asunaprevir (ASV) for 24 weeks in real-world HCV genotype 1-infected Japanese individuals. Methods. After screening for HCV NS5A resistance-associated variants (RAVs) by PCR invader assay, a total of 54 Japanese patients infected with HCV genotype 1 treated with DCV plus ASV were retrospectively analyzed...
2016: International Journal of Medical Sciences
Xue Chen, Ann M Bode, Zigang Dong, Ya Cao
The epithelial-mesenchymal transition (EMT), defined as transdifferentiation of epithelial cells into mesenchymal cells, is critical for embryonic development, wound healing, tissue regeneration, organ fibrosis, and cancer progression. Recently, the role of EMT in carcinogenesis has attracted much attention. Oncoviruses, including human papillomaviruses (HPVs), Epstein-Barr virus (EBV), and hepatitis B and C viruses (HBVs, HCVs), are known to be involved in the etiology of cancer and have been found to play important roles in cancer metastasis, especially in the EMT process...
September 2016: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Avik Biswas, Jason Treadaway, Timothy L Tellinghuisen
UNLABELLED: The hepatitis C virus NS5A protein is tethered to cellular membranes via an amphipathic amino-terminal helix that is inserted in-plane into the outer endoplasmic reticulum (ER)-derived membrane leaflet. The charged face of the helix faces the cytoplasm and may contribute to interactions involved in replicase assembly and function. Using an aggressive charge flip mutagenesis strategy, we identified a number of essential residues for replication on the charged face of the NS5A anchor and identified a double charge face mutant that is lethal for RNA replication but generates suppressor mutations in the carboxy-terminal helix of the NS4B protein...
August 15, 2016: Journal of Virology
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