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Flavivirus NS3

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https://www.readbyqxmd.com/read/29745301/comparative-genome-analysis-of-alkhumra-hemorrhagic-fever-virus-with-kyasanur-forest-disease-and-tick-borne-encephalitis-viruses-by-the-in-silico-approach
#1
Navaneethan Palanisamy, Dario Akaberi, Johan Lennerstrand, Åke Lundkvist
Alkhumra hemorrhagic fever virus (AHFV), a relatively new member of the Flaviviruses, was discovered in Saudi Arabia 23 years ago. AHFV is classified in the tick-borne encephalitis virus serocomplex, along with the Kyasanur forest disease virus (KFDV) and tick-borne encephalitis virus (TBEV). Currently, very little is known about the pathologies of AHFV. In this study, using the available genome information of AHFV, KFDV and TBEV, we have predicted and compared the following aspects of these viruses: evolution, nucleotide and protein compositions, recombination, codon frequency, substitution rate, N- and O-glycosylation sites, signal peptide and cleavage site, transmembrane region, secondary structure of 5' and 3' UTRs and RNA-RNA interactions...
May 10, 2018: Pathogens and Global Health
https://www.readbyqxmd.com/read/29665375/luteolin-escape-mutants-of-dengue-virus-map-to-prm-and-ns2b-and-reveal-viral-plasticity-during-maturation
#2
Minhua Peng, Crystall Marie Dawn Swarbrick, Kitti Wing-Ki Chan, Dahai Luo, Wei Zhang, Xiaoping Lai, Geng Li, Subhash G Vasudevan
We previously showed that luteolin, a well-known plant-derived component found in the "heat clearing" class of Traditional Chinese Medicine (TCM) herbs, is an uncompetitive inhibitor (Ki 58.6 μM) of the host proprotein convertase furin, an endoprotease that is required for maturation of flaviviruses in the trans-Golgi compartment. Luteolin also weakly inhibited recombinant dengue virus NS2B/NS3 protease (Ki 140.36 μM) non-competitively. In order to further explore the mechanism of inhibition we isolated resistant mutants by continuous passaging of DENV2 in the presence of increasing concentrations of luteolin...
April 14, 2018: Antiviral Research
https://www.readbyqxmd.com/read/29495257/a-fluorescent-cell-based-system-for-imaging-zika-virus-infection-in-real-time
#3
Michael J McFadden, Aaron Mitchell-Dick, Christine Vazquez, Allison E Roder, Kevin F Labagnara, John J McMahon, Debra L Silver, Stacy M Horner
Zika virus (ZIKV) is a re-emerging flavivirus that is transmitted to humans through the bite of an infected mosquito or through sexual contact with an infected partner. ZIKV infection during pregnancy has been associated with numerous fetal abnormalities, including prenatal lethality and microcephaly. However, until recent outbreaks in the Americas, ZIKV has been relatively understudied, and therefore the biology and pathogenesis of ZIKV infection remain incompletely understood. Better methods to study ZIKV infection in live cells could enhance our understanding of the biology of ZIKV and the mechanisms by which ZIKV contributes to fetal abnormalities...
February 24, 2018: Viruses
https://www.readbyqxmd.com/read/29330423/t-cell-immunity-to-zika-virus-targets-immunodominant-epitopes-that-show-cross-reactivity-with-other-flaviviruses
#4
C J Reynolds, O M Suleyman, A M Ortega-Prieto, J K Skelton, P Bonnesoeur, A Blohm, V Carregaro, J S Silva, E A James, B Maillère, M Dorner, R J Boyton, D M Altmann
Zika virus (ZIKV) Infection has several outcomes from asymptomatic exposure to rash, conjunctivitis, Guillain-Barré syndrome or congenital Zika syndrome. Analysis of ZIKV immunity is confounded by the fact that several related Flaviviruses infect humans, including Dengue virus 1-4, West Nile virus and Yellow Fever virus. HLA class II restricted T cell cross-reactivity between ZIKV and other Flaviviruses infection(s) or vaccination may contribute to protection or to enhanced immunopathology. We mapped immunodominant, HLA class II restricted, CD4 epitopes from ZIKV Envelope (Env), and Non-structural (NS) NS1, NS3 and NS5 antigens in HLA class II transgenic mice...
January 12, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29321318/viperin-restricts-zika-virus-and-tick-borne-encephalitis-virus-replication-by-targeting-ns3-for-proteasomal-degradation
#5
Christakis Panayiotou, Richard Lindqvist, Chaitanya Kurhade, Kirstin Vonderstein, Jenny Pasto, Karin Edlund, Arunkumar S Upadhyay, Anna K Överby
Flaviviruses are arthropod-borne viruses that constitute a major global health problem, with millions of human infections annually. Their pathogenesis ranges from mild illness to severe manifestations such as hemorrhagic fever and fatal encephalitis. Type I interferons (IFNs) are induced in response to viral infection and stimulate the expression of interferon-stimulated genes (ISGs), including that encoding viperin (virus-inhibitory protein, endoplasmic reticulum associated, IFN inducible), which shows antiviral activity against a broad spectrum of viruses, including several flaviviruses...
April 1, 2018: Journal of Virology
https://www.readbyqxmd.com/read/29321308/sustained-specific-and-cross-reactive-t-cell-responses-to-zika-and-dengue-virus-ns3-in-west-africa
#6
Bobby Brooke Herrera, Wen-Yang Tsai, Charlotte A Chang, Donald J Hamel, Wei-Kung Wang, Yichen Lu, Souleymane Mboup, Phyllis J Kanki
Recent studies on the role of T cells in Zika virus (ZIKV) infection have shown that T cell responses to Asian ZIKV infection are important for protection, and that previous dengue virus (DENV) exposure amplifies the protective T cell response to Asian ZIKV. Human T cell responses to African ZIKV infection, however, remain unexplored. Here, we utilized the modified anthrax toxin delivery system to develop a flavivirus enzyme-linked immunosorbent spot (ELISPOT) assay. Using human ZIKV and DENV samples from Senegal, West Africa, our results demonstrate specific and cross-reactive T cell responses to nonstructural protein 3 (NS3)...
April 1, 2018: Journal of Virology
https://www.readbyqxmd.com/read/29288700/erythrosin-b-is-a-potent-and-broad-spectrum-orthosteric-inhibitor-of-the-flavivirus-ns2b-ns3-protease
#7
Zhong Li, Srilatha Sakamuru, Ruili Huang, Matthew Brecher, Cheri A Koetzner, Jing Zhang, Haiying Chen, Cheng-Feng Qin, Qing-Yu Zhang, Jia Zhou, Laura D Kramer, Menghang Xia, Hongmin Li
Many flaviviruses, such as Zika virus (ZIKV), Dengue virus (DENV1-4) and yellow fever virus (YFV), are significant human pathogens. Infection with ZIKV, an emerging mosquito-borne flavivirus, is associated with increased risk of microcephaly in newborns and Guillain-Barré syndrome and other complications in adults. Currently, specific therapy does not exist for any flavivirus infections. In this study, we found that erythrosin B, an FDA-approved food additive, is a potent inhibitor for flaviviruses, including ZIKV and DENV2...
February 2018: Antiviral Research
https://www.readbyqxmd.com/read/29165589/ns3-helicase-from-dengue-virus-specifically-recognizes-viral-rna-sequence-to-ensure-optimal-replication
#8
Crystall M D Swarbrick, Chandrakala Basavannacharya, Kitti W K Chan, Shu-Ann Chan, Daljit Singh, Na Wei, Wint Wint Phoo, Dahai Luo, Julien Lescar, Subhash G Vasudevan
The protein-RNA interactions within the flavivirus replication complex (RC) are not fully understood. Our structure of dengue virus NS3 adenosine triphosphatase (ATPase)/helicase bound to the conserved 5' genomic RNA 5'-AGUUGUUAGUCU-3' reveals that D290 and R538 make specific interactions with G2 and G5 bases respectively. We show that single-stranded 12-mer RNA stimulates ATPase activity of NS3, however the presence of G2 and G5 leads to significantly higher activation. D290 is adjacent to the DEXH motif found in SF2 helicases like NS3 and interacts with R387, forming a molecular switch that activates the ATPase site upon RNA binding...
December 15, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/29141913/multiplexed-biomarker-panels-discriminate-zika-and-dengue-virus-infection-in-humans
#9
Guang Song, Hee-Sool Rho, Jianbo Pan, Pedro Ramos, Ki-Jun Yoon, Freddy A Medina, Emily M Lee, Daniel Eichinger, Guo-Li Ming, Jorge L Muñoz-Jordan, Hengli Tang, Ignacio Pino, Hongjun Song, Jiang Qian, Heng Zhu
Zika virus (ZIKV) and dengue virus (DENV) are closely related flaviviruses that cause widespread, acute febrile illnesses, notably microcephaly for fetuses of infected pregnant women. Detecting the viral cause of these illnesses is paramount to determine risks to patients, counsel pregnant women, and help fight outbreaks. A combined diagnostic algorithm for ZIKV and DENV requires Reverse transcription polymerase chain reaction (RT-PCR) and IgM antibody detection. RT-PCR differentiates between DENV and ZIKV infections during the acute phases of infection, but differentiation based on IgM antibodies is currently nearly impossible in endemic areas...
February 2018: Molecular & Cellular Proteomics: MCP
https://www.readbyqxmd.com/read/29099073/helicase-domain-of-west-nile-virus-ns3-protein-plays-a-role-in-inhibition-of-type-i-interferon-signalling
#10
Yin Xiang Setoh, Parthiban Periasamy, Nias Yong Gao Peng, Alberto A Amarilla, Andrii Slonchak, Alexander A Khromykh
West Nile virus (WNV) is a neurotropic flavivirus that can cause encephalitis in mammalian and avian hosts. In America, the virulent WNV strain (NY99) is causing yearly outbreaks of encephalitis in humans and horses, while in Australia the less virulent Kunjin strain of WNV strain has not been associated with significant disease outbreaks until a recent 2011 large outbreak in horses (but not in humans) caused by NSW2011 strain. Using chimeric viruses between NY99 and NSW2011 strains we previously identified a role for the non-structural proteins of NY99 strain and especially the NS3 protein, in enhanced virus replication in type I interferon response-competent cells and increased virulence in mice...
November 2, 2017: Viruses
https://www.readbyqxmd.com/read/29070684/ns3-from-hepatitis-c-virus-strain-jfh-1-is-an-unusually-robust-helicase-that-is-primed-to-bind-and-unwind-viral-rna
#11
Ting Zhou, Xiaoming Ren, Rebecca L Adams, Anna Marie Pyle
Hepatitis C viruses (HCV) encode a helicase enzyme that is essential for viral replication and assembly (nonstructural protein 3 [NS3]). This helicase has become the focus of extensive basic research on the general helicase mechanism, and it is also of interest as a novel drug target. Despite the importance of this protein, mechanistic work on NS3 has been conducted almost exclusively on variants from HCV genotype 1. Our understanding of NS3 from the highly active HCV strains that are used to study HCV genetics and mechanism in cell culture (such as JFH-1) is lacking...
January 1, 2018: Journal of Virology
https://www.readbyqxmd.com/read/28951254/protein-backbone-flexibility-pattern-is-evolutionarily-conserved-in-the-flaviviridae-family-a-case-of-ns3-protease-in-flavivirus-and-hepacivirus
#12
Navaneethan Palanisamy, Dario Akaberi, Johan Lennerstrand
Viruses belonging to the Flaviviridae family have been an important health concern for humans, animals and birds alike. No specific treatment is available yet for many of the viral infections caused by the members of this family. Lack of specific drugs against these viruses is mainly due to lack of protein structure information. It has been known that protein backbone fluctuation pattern is highly conserved in protein pairs with similar folds, in spite of the lack of sequence similarity. We hypothesized that this concept should also hold true for proteins (especially enzymes) of viruses included in different genera of the Flaviviridae family, as we know that the sequence similarity between them is low...
January 2018: Molecular Phylogenetics and Evolution
https://www.readbyqxmd.com/read/28927677/std-nmr-experiments-identify-a-structural-motif-with-novel-second-site-activity-against-west-nile-virus-ns2b-ns3-protease
#13
Tobias Schöne, Lena Lisbeth Grimm, Naoki Sakai, Linlin Zhang, Rolf Hilgenfeld, Thomas Peters
West Nile virus (WNV) belongs to the genus Flavivirus of the family Flaviviridae. This mosquito-borne virus that is highly pathogenic to humans has been evolving into a global threat during the past two decades. Despite many efforts, neither antiviral drugs nor vaccines are available. The viral protease NS2B-NS3(pro) is essential for viral replication, and therefore it is considered a prime drug target. However, success in the development of specific NS2B-NS3(pro) inhibitors had been moderate so far. In the search for new structural motifs with binding affinity for NS2B-NS3(pro), we have screened a fragment library, the Maybridge Ro5 library, employing saturation transfer difference (STD) NMR experiments as readout...
September 18, 2017: Antiviral Research
https://www.readbyqxmd.com/read/28919920/virulence-determinants-of-west-nile-virus-how-can-these-be-used-for-vaccine-design
#14
REVIEW
Jaclyn A Kaiser, Tian Wang, Alan Dt Barrett
West Nile virus (WNV), a neurotropic mosquito-borne flavivirus, has become endemic in the USA and parts of Europe since 1999. There is no licensed WNV vaccine for humans. Considering the robust immunity from immunization with live, attenuated vaccines, a live WNV vaccine is an ideal platform for disease control. Animal and mosquito studies have identified a number of candidate attenuating mutations, including the structural proteins premembrane/membrane and envelope, and the nonstructural proteins NS1, NS2A, NS3, NS4A, NS4B and NS5, and the 3' UTR...
May 2017: Future Virology
https://www.readbyqxmd.com/read/28916391/zika-virus-structural-biology-and-progress-in-vaccine-development
#15
REVIEW
Hsiao-Han Lin, Bak-Sau Yip, Li-Min Huang, Suh-Chin Wu
The growing number of zika virus (ZIKV) infections plus a 20-fold increase in neonatal microcephaly in newborns in Brazil have raised alarms in many countries regarding the threat to pregnant women. Instances of microcephaly and central nervous system malformations continue to increase in ZIKV outbreak regions. ZIKV is a small enveloped positive-strand RNA virus belonging to the Flavivirus genus of the Flaviviridae family. High-resolution ZIKV structures recently identified by cryo-electron microscopy indicate that the overall ZIKV structure is similar to those of other flaviviruses...
January 2018: Biotechnology Advances
https://www.readbyqxmd.com/read/28816628/outbreak-and-cocirculation-of-three-different-usutu-virus-strains-in-eastern-germany
#16
Michael Sieg, Volker Schmidt, Ute Ziegler, Markus Keller, Dirk Höper, Kristin Heenemann, Antje Rückner, Hermann Nieper, Aemero Muluneh, Martin H Groschup, Thomas W Vahlenkamp
Usutu virus (USUV) is a mosquito-borne flavivirus accounting for large-scale deaths in resident bird populations. In this study, we show the introduction of USUV to Eastern Germany resulting in massive death of birds, particularly blackbirds (Turdus merula). We found that three diverse USUV lineages ("Europe 3," "Africa 2," and "Africa 3-like") circulated simultaneously. Moreover, we detected USUV in Culex pipiens in a region where no dead birds were reported, strengthening the need for mosquito monitoring to uncover the spread of arboviruses...
September 2017: Vector Borne and Zoonotic Diseases
https://www.readbyqxmd.com/read/28815931/organization-of-the-flavivirus-rna-replicase-complex
#17
REVIEW
Carolin Brand, Martin Bisaillon, Brian J Geiss
Flaviviruses, such as dengue, Japanese encephalitis, West Nile, yellow fever, and Zika viruses, are serious human pathogens that cause significant morbidity and mortality globally each year. Flaviviruses are single-stranded, positive-sense RNA viruses, and encode two multidomain proteins, NS3 and NS5, that possess all enzymatic activities required for genome replication and capping. NS3 and NS5 interact within virus-induced replication compartments to form the RNA genome replicase complex. Although the individual enzymatic activities of both proteins have been extensively studied and are well characterized, there are still gaps in our understanding of how they interact to efficiently coordinate their respective activities during positive-strand RNA synthesis and capping...
November 2017: Wiley Interdisciplinary Reviews. RNA
https://www.readbyqxmd.com/read/28689970/structural-dynamics-of-zika-virus-ns2b-ns3-protease-binding-to-dipeptide-inhibitors
#18
Yan Li, Zhenzhen Zhang, Wint Wint Phoo, Ying Ru Loh, Weiling Wang, Shuang Liu, Ming Wei Chen, Alvin W Hung, Thomas H Keller, Dahai Luo, CongBao Kang
The NS2B-NS3 viral protease is an attractive drug target against Zika virus (ZIKV) due to its importance in viral replication and maturation. Here we report the crystal structure of protease in complex with a dipeptide inhibitor, Acyl-KR-aldehyde (compound 1). The aldehyde moiety forms a covalent bond with the catalytic Ser(135) of NS3. The Arg and Lys residues in the inhibitor occupy the S1 and S2 sites of the protease, respectively. Nuclear magnetic resonance studies demonstrate that the complex is in the closed conformation in solution...
August 1, 2017: Structure
https://www.readbyqxmd.com/read/28685770/existing-drugs-as-broad-spectrum-and-potent-inhibitors-for-zika-virus-by-targeting-ns2b-ns3-interaction
#19
Zhong Li, Matthew Brecher, Yong-Qiang Deng, Jing Zhang, Srilatha Sakamuru, Binbin Liu, Ruili Huang, Cheri A Koetzner, Christina A Allen, Susan A Jones, Haiying Chen, Na-Na Zhang, Min Tian, Fengshan Gao, Qishan Lin, Nilesh Banavali, Jia Zhou, Nathan Boles, Menghang Xia, Laura D Kramer, Cheng-Feng Qin, Hongmin Li
Recent outbreaks of Zika virus (ZIKV) highlight an urgent need for therapeutics. The protease complex NS2B-NS3 plays essential roles during flaviviral polyprotein processing, and thus represents an attractive drug target. Here, we developed a split luciferase complementation-based high-throughput screening assay to identify orthosteric inhibitors that directly target flavivirus NS2B-NS3 interactions. By screening a total of 2 816 approved and investigational drugs, we identified three potent candidates, temoporfin, niclosamide, and nitazoxanide, as flavivirus NS2B-NS3 interaction inhibitors with nanomolar potencies...
August 2017: Cell Research
https://www.readbyqxmd.com/read/28592527/zika-virus-hijacks-stress-granule-proteins-and-modulates-the-host-stress-response
#20
Shangmei Hou, Anil Kumar, Zaikun Xu, Adriana M Airo, Iryna Stryapunina, Cheung Pang Wong, William Branton, Egor Tchesnokov, Matthias Götte, Christopher Power, Tom C Hobman
Zika virus (ZIKV), a member of the Flaviviridae family, has recently emerged as an important human pathogen with increasing economic and health impact worldwide. Because of its teratogenic nature and association with the serious neurological condition Guillain-Barré syndrome, a tremendous amount of effort has focused on understanding ZIKV pathogenesis. To gain further insights into ZIKV interaction with host cells, we investigated how this pathogen affects stress response pathways. While ZIKV infection induces stress signaling that leads to phosphorylation of eIF2α and cellular translational arrest, stress granule (SG) formation was inhibited...
June 7, 2017: Journal of Virology
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