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John T Randolph, Charles A Flentge, Pamela Donner, Todd W Rockway, Sachin V Patel, Lissa Nelson, Douglas K Hutchinson, Rubina Mondal, Neeta Mistry, Thomas Reisch, Tatyana Dekhtyar, Preethi Krishnan, Tami Pilot-Matias, Deanne F Stolarik, David W A Beno, Rolf Wagner, Clarence Maring, Warren M Kati
Research toward a next-generation HCV NS5A inhibitor has identified fluorobenzimidazole analogs that demonstrate potent, broad-genotype in vitro activity against HCV genotypes 1-6 replicons as well as HCV NS5A variants that are orders of magnitude less susceptible to inhibition by first-generation NS5A inhibitors in comparison to wild-type replicons. The fluorobenzimidazole inhibitors have improved pharmacokinetic properties in comparison to non-fluorinated benzimidazole analogs. Discovery of these inhibitors was facilitated by exploring SAR in a structurally simplified inhibitor series...
October 13, 2016: Bioorganic & Medicinal Chemistry Letters
Yanzhao Chen, Baihai Jiao, Min Yao, Xuezhen Shi, Zhebin Zheng, Shilin Li, Limin Chen
Interferon stimulated (sensitive) genes (ISGs) are the effector molecules downstream of type I/III interferon (IFN) signaling pathways in host innate immunity. ISG12a can be induced by IFN-α. Although ISG12a has been reported to inhibit the replication of HCV, the exact mechanism remains to be determined. In this study, we investigated the possible mechanisms of ISG12a anti- HCV property by exploring the production of type I IFN and the activation of Janus kinase/signal transducer and activator of transcription (Jak/STAT) signaling pathway, apoptosis and autophagy in Huh7...
October 21, 2016: Virus Research
Kaihang Wang, Julius Fredens, Simon F Brunner, Samuel H Kim, Tiongsun Chia, Jason W Chin
Synthetic recoding of genomes, to remove targeted sense codons, may facilitate the encoded cellular synthesis of unnatural polymers by orthogonal translation systems. However, our limited understanding of allowed synonymous codon substitutions, and the absence of methods that enable the stepwise replacement of the Escherichia coli genome with long synthetic DNA and provide feedback on allowed and disallowed design features in synthetic genomes, have restricted progress towards this goal. Here we endow E. coli with a system for efficient, programmable replacement of genomic DNA with long (>100-kb) synthetic DNA, through the in vivo excision of double-stranded DNA from an episomal replicon by CRISPR/Cas9, coupled to lambda-red-mediated recombination and simultaneous positive and negative selection...
October 24, 2016: Nature
Minji Yang, GilJae Lee, Jiyeon Si, Sung-Joon Lee, Hyun Ju You, GwangPyo Ko
Phytochemicals provide environmentally friendly and relatively inexpensive natural products, which could potentially benefit public health by controlling human norovirus (HuNoV) infection. In this study, 18 different phytochemicals were evaluated for antiviral effects against norovirus using murine norovirus (MNV) as a model for norovirus biology. Among these phytochemicals, curcumin (CCM) was the most potent anti-noroviral phytochemical, followed by resveratrol (RVT). In a cell culture infection model, exposure to CCM or RVT for 3 days reduced infectivity of norovirus by 91% and 80%, respectively...
October 20, 2016: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Hyun-Ji Park, Eun Je Jeon, Jung Seung Lee, Sang Hyeon Hong, Ann-Na Cho, Joan Lee, Jae-Su Moon, Kyeong-Eun Jung, Jong-Won Oh, Haeshin Lee, Seung-Woo Cho
Small interfering RNA (siRNA) delivery can provide an effective therapy for treating viral diseases by silencing genes involved in viral replication. In this study, a liver-targeting formulation of lipidoid nanoparticle for delivery of siRNA that targets protein kinase C-related kinase 2 (PRK2) to inhibit hepatitis C virus (HCV) replication is reported. The most effective, minimally cytotoxic lipidoid for siRNA delivery to hepatic cells is identified from a small library of alkyl epoxide-polyamine conjugates...
October 24, 2016: Advanced Healthcare Materials
Robert N Kirchdoerfer, Crystal L Moyer, Dafna M Abelson, Erica Ollmann Saphire
Filoviruses are capable of causing deadly hemorrhagic fevers. All nonsegmented negative-sense RNA-virus nucleocapsids are composed of a nucleoprotein (NP), a phosphoprotein (VP35) and a polymerase (L). However, the VP30 RNA-synthesis co-factor is unique to the filoviruses. The assembly, structure, and function of the filovirus RNA replication complex remain unclear. Here, we have characterized the interactions of Ebola, Sudan and Marburg virus VP30 with NP using in vitro biochemistry, structural biology and cell-based mini-replicon assays...
October 2016: PLoS Pathogens
Wenyao Chen, Tingzi Fang, Xiujuan Zhou, Daofeng Zhang, Xianming Shi, Chunlei Shi
The wide usage of antibiotics contributes to the increase in the prevalence of antibiotic-resistant Salmonella. Plasmids play a critical role in horizontal transfer of antibiotic resistance markers in Salmonella. This study aimed to screen and characterize plasmid profiles responsible for antibiotic resistance in Salmonella and ultimately to clarify the molecular mechanism of transferable plasmid-mediated antibiotic resistance. A total of 226 Salmonella isolates were examined for antimicrobial susceptibility by a disk diffusion method...
2016: Frontiers in Microbiology
Dorota Korsak, Magdalena Szuplewska
A total of 127 Listeria isolates from food and food processing environments, including 75 L. innocua, 49 L. welshimeri, 2 L. seeligeri and 1L. grayi were tested for susceptibility to eight antimicrobials, benzalkonium chloride (BC), cadmium and arsenic. The isolates were also screened for the presence of extrachromosomal genetic elements - plasmids, and their restriction pattern types were determined. All strains were susceptible to ampicillin, ciprofloxacin, erythromycin, gentamicin, rifampicin, trimethoprim and vancomycin...
December 5, 2016: International Journal of Food Microbiology
D N Tran, H H Tran, M Matsui, M Suzuki, S Suzuki, K Shibayama, T D Pham, T T Van Phuong, D A Dang, H S Trinh, C T Loan, L T V Nga, H R van Doorn, H F L Wertheim
Acinetobacter baumannii is an important cause of multidrug-resistant hospital acquired infections in the world. Here, we investigate the presence of NDM-1 and other carbapenemases among carbapenem-resistant A. baumannii isolated between August 2010 and December 2014 from three large hospitals in Hanoi, Vietnam. We identified 23/582 isolates (4 %) (11 from hospital A, five from hospital B, and seven from hospital C) that were NDM-1 positive, and among them 18 carried additional carbapenemase genes, including seven isolates carrying NDM-1, IMP-1, and OXA-58 with high MICs for carbapenems...
October 6, 2016: European Journal of Clinical Microbiology & Infectious Diseases
Marta Irla, Tonje M B Heggeset, Ingemar Nærdal, Lidia Paul, Tone Haugen, Simone B Le, Trygve Brautaset, Volker F Wendisch
Bacillus methanolicus is a thermophilic methylotroph able to overproduce amino acids from methanol, a substrate not used for human or animal nutrition. Based on our previous RNA-seq analysis a mannitol inducible promoter and a putative mannitol activator gene mtlR were identified. The mannitol inducible promoter was applied for controlled gene expression using fluorescent reporter proteins and a flow cytometry analysis, and improved by changing the -35 promoter region and by co-expression of the mtlR regulator gene...
2016: Frontiers in Microbiology
B Fevery, T Verbinnen, M Peeters, K Janssen, J Witek, W Jessner, S De Meyer, O Lenz
Simeprevir is a hepatitis C virus NS3/4A protease inhibitor. Hepatitis C virus baseline NS3/4A polymorphisms and emerging mutations were characterized in treatment-naїve and treatment-experienced genotype 4-infected patients treated with simeprevir+peginterferon/ribavirin in the RESTORE study. Population sequencing of the NS3/4A region was performed and in vitro simeprevir activity against site-directed mutants or chimeric replicons with patient-derived NS3 protease sequences was assessed in a transient replicon assay...
October 3, 2016: Journal of Viral Hepatitis
Chawin Mongkolsiriwattana, Jaclyn S Zhou, James C K Ng
The terminal ends in the genome of RNA viruses contain features that regulate viral replication and/or translation. We have identified a Y-shaped structure (YSS) in the 3' terminal regions of the bipartite genome of Lettuce chlorosis virus (LCV), a member in the genus Crinivirus (family Closteroviridae). The YSS is the first in this family of viruses to be determined using Selective 2'-Hydroxyl Acylation Analyzed by Primer Extension (SHAPE). Using luciferase constructs/replicons, in vivo and in vitro assays showed that the 5' and YSS-containing 3' terminal regions of LCV RNA1 supported translation activity...
October 3, 2016: Scientific Reports
Jenny Wachter, Stuart A Hill
As virulence often correlates with the presence of plasmid replicons in several Vibrio spp., this study investigated whether non-chromosomal DNA could be found in the coral pathogen, Vibrio coralliilyticus BAA-450. A circular plasmid, 26,631 bp in size, was identified. DNA sequence analysis indicated that the plasmid contained 30 open reading frames, six tRNA genes, 12 inverted repeats, three direct repeats and presented no continuous sequence identity to other replicons within the database. Consequently, these findings indicate that this is a novel, previously unidentified, plasmid...
January 4, 2016: Microorganisms
Ling Tong, Wensheng Yu, Craig A Coburn, Lei Chen, Oleg Selyutin, Qingbei Zeng, Michael P Dwyer, Anilkumar G Nair, Bandarpalle B Shankar, Seong Heon Kim, De-Yi Yang, Stuart B Rosenblum, Rebecca T Ruck, Ian W Davies, Bin Hu, Bin Zhong, Jinglai Hao, Tao Ji, Shuai Zan, Rong Liu, Sony Agrawal, Donna Carr, Stephanie Curry, Patricia McMonagle, Karin Bystol, Frederick Lahser, Paul Ingravallo, Shiying Chen, Ernest Asante-Appiah, Joseph A Kozlowski
We describe the impact of proline modifications, in our tetracyclic-indole based series of nonstructural protein 5A (NS5A) inhibitors, to their replicon profiles. This work identified NS5A inhibitors with an improved and flattened resistance profiles.
September 2, 2016: Bioorganic & Medicinal Chemistry Letters
Ken-Ichi Mori, Akihiro Matsumoto, Noboru Maki, Yuki Ichikawa, Eiji Tanaka, Shintaro Yagi
BACKGROUND: Despite the high prevalence of genotype 1b hepatitis C virus (HCV) among patients, a cell culture system that permits entire viral life cycle of genotype 1b isolates is limited. To develop a cell-cultured hepatitis C virus (HCVcc) of genotype 1b, the proper combination of HCV genomic variants and host cells is essential. HCV genomes isolated from patients with distinctive symptoms may provide the variants required to establish an HCVcc of genotype 1b. RESULTS: We first established subgenomic replicons in Huh7 cells using HCV cDNAs isolated from two patients: one with fulminant hepatitis after liver transplantation (TPF1) and another with acute hepatitis and moderate symptoms (sAH)...
September 27, 2016: BMC Microbiology
Bruce McCollister, Cassandra V Kotter, Daniel N Frank, Taylor Washburn, Michael G Jobling
We report a case of ceftriaxone (CTX) treatment failure for bacteremia caused by Salmonella enterica subsp. enterica serovar Typhimurium, due to the in vivo acquisition of a blaCTX-M-27-encoding IncFII group transmissible plasmid. The original β-lactamase-susceptible isolate ST882S was replaced by the resistant isolate ST931R during ceftriaxone treatment. After relapse, treatment was changed to ciprofloxacin and the patient recovered. Isolate ST931R could transfer resistance to E. coli at 37 °C. We used whole-genome sequencing of ST882S and ST931R, the E...
September 26, 2016: Antimicrobial Agents and Chemotherapy
Yoko Tsukuda, Goki Suda, Seiji Tsunematsu, Jun Ito, Fumiyuki Sato, Katsumi Terashita, Masato Nakai, Takuya Sho, Osamu Maehara, Tomoe Shimazaki, Megumi Kimura, Kenichi Morikawa, Mitsuteru Natsuizaka, Koji Ogawa, Shunsuke Ohnishi, Makoto Chuma, Naoya Sakamoto
Hepatitis C virus (HCV) has been reported to hijack fatty acid metabolism in infected hepatocytes, taking advantage of lipid droplets for virus assembly. In this study, we analyzed the anti-HCV activity of l-carnitine, a substance involved in the transport of fatty acids into mitochondria. JFH-1 or HCV replicon-transfected Huh7.5.1 cells were treated with or without l-carnitine to examine its anti-HCV effects. The effects of l-carnitine on HCV entry, HCV-induced adipogenesis and lipid droplet formation, and HCV-induced oxidative stress were examined...
September 24, 2016: Journal of Medical Virology
Beatrice Conti, Cristiana Porcu, Carmela Viscomi, Antonella Minutolo, Susan Costantini, Marco Corazzari, Gino Iannucci, Barbara Barbaro, Clara Balsano
HCV life cycle is strictly correlated with the hepatocyte lipid metabolism; moreover, the progression of HCV chronic hepatitis is accelerated by the presence of liver steatosis. Among the steatogenic genes deregulated during the HCV infection one of the most attractive is the Small Heterodimer Protein 1 (SHP1; NR0B2), that is involved in a remarkable number of metabolic functions. HCV NS5A is an essential and integral component of the HCV membranous-web replicon complex (RC) and plays an essential role to transfer the viral genome from the RCs to the surface of the lipid droplets (LDs) that, in turn, play a key function during HCV life cycle...
September 20, 2016: Oncotarget
Xuping Xie, Jing Zou, Chao Shan, Yujiao Yang, Dieudonné Buh Kum, Kai Dallmeier, Johan Neyts, Pei-Yong Shi
The current epidemic of Zika virus (ZIKV) has underscored the urgency to establish experimental systems for studying viral replication and pathogenesis, and countermeasure development. Here we report two ZIKV replicon systems: a luciferase replicon that can differentiate between viral translation and RNA synthesis; and a stable luciferase replicon carrying cell line that can be used to screen and characterize inhibitors of viral replication. The transient replicon was used to evaluate the effect of an NS5 polymerase mutation on viral RNA synthesis and to analyze a known ZIKV inhibitor...
September 14, 2016: EBioMedicine
Jens Bukh
The discovery of hepatitis C virus (HCV) in 1989 permitted basic research to unravel critical components of a complex life cycle for this important human pathogen. HCV is a highly divergent group of viruses classified in 7 major genotypes and a great number of subtypes, and circulating in infected individuals as a continuously evolving quasispecies destined to escape host immune responses and applied antivirals. Despite the inability to culture patient viruses directly in the laboratory, efforts to define the infectious genome of HCV resulted in development of experimental recombinant in vivo and in vitro systems, including replicons and infectious cultures in human hepatoma cell lines...
October 2016: Journal of Hepatology
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