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Flavivirus NS3

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https://www.readbyqxmd.com/read/28919920/virulence-determinants-of-west-nile-virus-how-can-these-be-used-for-vaccine-design
#1
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
#2
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...
September 12, 2017: Biotechnology Advances
https://www.readbyqxmd.com/read/28816628/outbreak-and-cocirculation-of-three-different-usutu-virus-strains-in-eastern-germany
#3
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
#4
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...
August 16, 2017: Wiley Interdisciplinary Reviews. RNA
https://www.readbyqxmd.com/read/28689970/structural-dynamics-of-zika-virus-ns2b-ns3-protease-binding-to-dipeptide-inhibitors
#5
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
#6
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
#7
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
https://www.readbyqxmd.com/read/28542603/a-conformational-switch-high-throughput-screening-assay-and-allosteric-inhibition-of-the-flavivirus-ns2b-ns3-protease
#8
Matthew Brecher, Zhong Li, Binbin Liu, Jing Zhang, Cheri A Koetzner, Adham Alifarag, Susan A Jones, Qishan Lin, Laura D Kramer, Hongmin Li
The flavivirus genome encodes a single polyprotein precursor requiring multiple cleavages by host and viral proteases in order to produce the individual proteins that constitute an infectious virion. Previous studies have revealed that the NS2B cofactor of the viral NS2B-NS3 heterocomplex protease displays a conformational dynamic between active and inactive states. Here, we developed a conformational switch assay based on split luciferase complementation (SLC) to monitor the conformational change of NS2B and to characterize candidate allosteric inhibitors...
May 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/28506240/inhibitors-compounds-of-the-flavivirus-replication-process
#9
REVIEW
Leidy L García, Leonardo Padilla, Jhon C Castaño
Flaviviruses are small viruses with single-stranded RNA, which include the yellow fever virus, dengue virus, West Nile virus, Japanese encephalitis virus, tick-borne encephalitis virus, and Zika virus; and are causal agents of the most important emerging diseases that have no available treatment to date. In recent years, the strategy has focused on the development of replication inhibitors of these viruses designed to act mainly by affecting the activity of enzyme proteins, such as NS3 and NS5, which perform important functions in the viral replication process...
May 15, 2017: Virology Journal
https://www.readbyqxmd.com/read/28461069/characterization-of-the-zika-virus-two-component-ns2b-ns3-protease-and-structure-assisted-identification-of-allosteric-small-molecule-antagonists
#10
Sergey A Shiryaev, Chen Farhy, Antonella Pinto, Chun-Teng Huang, Nicole Simonetti, Annie Elong Ngono, Antimone Dewing, Sujan Shresta, Anthony B Pinkerton, Piotr Cieplak, Alex Y Strongin, Alexey V Terskikh
The recent re-emergence of Zika virus (ZIKV)(1), a member of the Flaviviridae family, has become a global emergency. Currently, there are no effective methods of preventing or treating ZIKV infection, which causes severe neuroimmunopathology and is particularly harmful to the developing fetuses of infected pregnant women. However, the pathology induced by ZIKV is unique among flaviviruses, and knowledge of the biology of other family members cannot easily be extrapolated to ZIKV. Thus, structure-function studies of ZIKV proteins are urgently needed to facilitate the development of effective preventative and therapeutic agents...
July 2017: Antiviral Research
https://www.readbyqxmd.com/read/28457855/polysulfonate-suramin-inhibits-zika-virus-infection
#11
Chee Wah Tan, I-Ching Sam, Wei Lim Chong, Vannajan Sanghiran Lee, Yoke Fun Chan
Zika virus (ZIKV) is an arthropod-borne flavivirus that causes newborn microcephaly and Guillian-Barré syndrome in adults. No therapeutics are available to treat ZIKV infection or other flaviviruses. In this study, we explored the inhibitory effect of glycosaminoglycans and analogues against ZIKV infection. Highly sulfated heparin, dextran sulfate and suramin significantly inhibited ZIKV infection in Vero cells. De-sulfated heparin analogues lose inhibitory effect, implying that sulfonate groups are critical for viral inhibition...
April 27, 2017: Antiviral Research
https://www.readbyqxmd.com/read/28441781/dengue-virus-non-structural-protein-5
#12
REVIEW
Abbas El Sahili, Julien Lescar
The World Health Organization estimates that the yearly number of dengue cases averages 390 million. This mosquito-borne virus disease is endemic in over 100 countries and will probably continue spreading, given the observed trend in global warming. So far, there is no antiviral drug available against dengue, but a vaccine has been recently marketed. Dengue virus also serves as a prototype for the study of other pathogenic flaviviruses that are emerging, like West Nile virus and Zika virus. Upon viral entry into the host cell and fusion of the viral lipid membrane with the endosomal membrane, the viral RNA is released and expressed as a polyprotein, that is then matured into three structural and seven non-structural (NS) proteins...
April 24, 2017: Viruses
https://www.readbyqxmd.com/read/28342876/increased-activity-of-unlinked-zika-virus-ns2b-ns3-protease-compared-to-linked-zika-virus-protease
#13
Benjamin D Kuiper, Kristin Slater, Nicholas Spellmon, Joshua Holcomb, Prasanna Medapureddy, Kendall M Muzzarelli, Zhe Yang, Reuben Ovadia, Franck Amblard, Iulia A Kovari, Raymond F Schinazi, Ladislau C Kovari
Zika virus (ZIKV) is a flavivirus spread by daytime-active Aedes spp. mosquitoes such as A. aegypti and A. albopictus. Previously thought to be a mild infection, the latest ZIKV outbreak in the Americas is causally associated with more severe symptoms as well as severe birth defects, such as microcephaly. Currently no vaccine or antiviral exists. However, recent progress has demonstrated the viral NS2B/NS3 protease may be a suitable target for the development of small-molecule antiviral agents. To better understand the ZIKV protease, we expressed, purified, and characterized unlinked and linked NS2B/NS3 protease corresponding to an isolate from the recent outbreak in Puerto Rico...
March 22, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28341122/molecular-dynamics-simulations-of-zika-virus-ns3-helicase-insights-into-rna-binding-site-activity
#14
Melina Mottin, Rodolpho C Braga, Roosevelt A da Silva, Joao H Martins da Silva, Alexander L Perryman, Sean Ekins, Carolina Horta Andrade
America is still suffering with the outbreak of Zika virus (ZIKV) infection. Congenital ZIKV syndrome has already caused a public health emergency of international concern. However, there are still no vaccines to prevent or drugs to treat the infection caused by ZIKV. The ZIKV NS3 helicase (NS3h) protein is a promising target for drug discovery due to its essential role in viral genome replication. NS3h unwinds the viral RNA to enable the replication of the viral genome by the NS5 protein. NS3h contains two important binding sites: the NTPase binding site and the RNA binding site...
March 21, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28261172/the-complement-system-in-flavivirus-infections
#15
Jonas N Conde, Emiliana M Silva, Angela S Barbosa, Ronaldo Mohana-Borges
The incidence of flavivirus infections has increased dramatically in recent decades in tropical and sub-tropical climates worldwide, affecting hundreds of millions of people each year. The Flaviviridae family includes dengue, West Nile, Zika, Japanese encephalitis, and yellow fever viruses that are typically transmitted by mosquitoes or ticks, and cause a wide range of symptoms, such as fever, shock, meningitis, paralysis, birth defects, and death. The flavivirus genome is composed of a single positive-sense RNA molecule encoding a single viral polyprotein...
2017: Frontiers in Microbiology
https://www.readbyqxmd.com/read/28196656/a-cdna-clone-launched-platform-for-high-yield-production-of-inactivated-zika-vaccine
#16
Yujiao Yang, Chao Shan, Jing Zou, Antonio E Muruato, Diniz Nunes Bruno, Barbosa de Almeida Medeiros Daniele, Pedro F C Vasconcelos, Shannan L Rossi, Scott C Weaver, Xuping Xie, Pei-Yong Shi
A purified inactivated vaccine (PIV) using the Zika virus (ZIKV) Puerto Rico strain PRVABC59 showed efficacy in monkeys, and is currently in a phase I clinical trial. High-yield manufacture of this PIV is essential for its development and vaccine access. Here we report an infectious cDNA clone-launched platform to maximize its yield. A single NS1 protein substitution (K265E) was identified to increase ZIKV replication on Vero cells (a cell line approved for vaccine production) for both Cambodian FSS13025 and Puerto Rico PRVABC59 strains...
March 2017: EBioMedicine
https://www.readbyqxmd.com/read/28188791/structure-and-sequence-based-functional-annotation-of-zika-virus-ns2b-protein-computational-insights
#17
Daniel Aguilera-Pesantes, Miguel A Méndez
While Zika virus (ZIKV) outbreaks are a growing concern for global health, a deep understanding about the virus is lacking. Here we report a contribution to the basic science on the virus- a detailed computational analysis of the non structural protein NS2b. This protein acts as a cofactor for the NS3 protease (NS3Pro) domain that is important on the viral life cycle, and is an interesting target for drug development. We found that ZIKV NS2b cofactor is highly similar to other virus within the Flavivirus genus, especially to West Nile Virus, suggesting that it is completely necessary for the protease complex activity...
February 8, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28137230/proteases-in-mosquito-borne-diseases-new-avenues-in-drug-development
#18
REVIEW
A Pant, R Pasupureddy, V Pande, S Seshadri, R Dixit, K C Pandey
INTRODUCTION: Mosquito borne diseases continue to propagate and cause millions of deaths annually. They are caused either by protozoan parasites such as Plasmodium, Toxoplasma or by flaviviruses including Dengue and Zika. Among the proteome of such parasitic organisms, proteases play essential roles in events such as host invasion, hemoglobin hydrolysis, replication and immune evasion. Plasmepsin V (PMV), an endoplasmic reticulum resident aspartic protease of Plasmodium spp., is involved in the export of ~400 proteins containing the conserved Plasmodium Export Element motif (PEXEL)...
2017: Current Topics in Medicinal Chemistry
https://www.readbyqxmd.com/read/28102736/dengue-and-zika-viruses-subvert-reticulophagy-by-ns2b3-mediated-cleavage-of-fam134b
#19
Nicholas J Lennemann, Carolyn B Coyne
The endoplasmic reticulum (ER) is exploited by several diverse viruses during their infectious life cycles. Flaviviruses, including dengue virus (DENV) and Zika virus (ZIKV), utilize the ER as a source of membranes to establish their replication organelles and to facilitate their assembly and eventual maturation along the secretory pathway. To maintain normal homeostasis, host cells have evolved highly efficient processes to dynamically regulate the ER, such as through reticulophagy, a selective form of autophagy that leads to ER degradation...
February 2017: Autophagy
https://www.readbyqxmd.com/read/28034741/identification-of-novel-small-molecule-inhibitors-against-ns2b-ns3-serine-protease-from-zika-virus
#20
Hyun Lee, Jinhong Ren, Salvatore Nocadello, Amy J Rice, Isabel Ojeda, Samuel Light, George Minasov, Jason Vargas, Dhanapalan Nagarathnam, Wayne F Anderson, Michael E Johnson
Zika flavivirus infection during pregnancy appears to produce higher risk of microcephaly, and also causes multiple neurological problems such as Guillain-Barré syndrome. The Zika virus is now widespread in Central and South America, and is anticipated to become an increasing risk in the southern United States. With continuing global travel and the spread of the mosquito vector, the exposure is expected to accelerate, but there are no currently approved treatments against the Zika virus. The Zika NS2B/NS3 protease is an attractive drug target due to its essential role in viral replication...
March 2017: Antiviral Research
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