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Antiviral Research

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https://www.readbyqxmd.com/read/28093339/short-term-clinical-safety-profile-of-brincidofovir-a-favorable-benefit-risk-proposition-in-the-treatment-of-smallpox
#1
Greg Chittick, Marion Morrison, Thomas Brundage, W Garrett Nichols
Brincidofovir (BCV, CMX001) is an orally available, long-acting, broad-spectrum antiviral that has been evaluated in healthy subjects in Phase I studies and in hematopoietic cell transplant recipients and other immunocompromised patients in Phase II/III clinical trials for the prevention and treatment of cytomegalovirus and adenovirus infections. BCV has also shown in vitro activity against orthopoxviruses such as variola (smallpox) virus, and is under advanced development as a treatment for smallpox under the US FDA's 'Animal Rule'...
January 13, 2017: Antiviral Research
https://www.readbyqxmd.com/read/28093338/a-virus-like-particle-vaccination-strategy-expands-its-tolerance-to-h3n2-antigenic-drift-by-enhancing-neutralizing-antibodies-against-hemagglutinin-stalk
#2
Ji-Rong Yang, Chieh-Yu Cheng, Chih-Yuan Chen, Chao-Hua Lin, Chuan-Yi Kuo, Hsiang-Yi Huang, Fu-Ting Wu, Yu-Chih Yang, Chia-Ying Wu, Ming-Tsan Liu, Pei-Wen Hsiao
Seasonal influenza viruses impact public health annually due to their continual evolution. However, the current inactivated seasonal vaccines provide poor protection against antigenically drifted viruses and require periodical reformulation through hit-and-miss predictions about which strains will circulate during the next season. To reduce the impact caused by vaccine mismatch, we investigated the drift-tolerance of virus-like particles (VLP) as an improved vaccine candidate. The cross-protective humoral immunity elicited by the H3N2-VLP vaccine constructed for the 2011-2012 season was examined against viruses isolated from 2010 to 2015 in Taiwan evolving chronologically through clades 1, 4, 5, 3B and 3C, as well as viruses that were circulating globally in 2005, 2007 and 2009...
January 13, 2017: Antiviral Research
https://www.readbyqxmd.com/read/28093337/nk-cell-phenotypic-and-functional-shifts-coincide-with-specific-clinical-phases-in-the-natural-history-of-chronic-hbv-infection
#3
Rik A de Groen, Jun Hou, Gertine W van Oord, Zwier M A Groothuismink, Marieke van der Heide, Robert J de Knegt, André Boonstra
BACKGROUND: Chronic HBV infection can be divided into 4 distinct clinical phases: immune tolerant, immune active, inactive carrier, and HBeAg-negative hepatitis. Using a systems biology approach, we recently identified innate immune response components, specifically NK cells as a distinctive factor of specific HBV clinical phases. To expand on this study and identify the underlying immunological mechanisms, we performed a comprehensive profiling of NK cells in chronic HBV infection. METHODS: Peripheral blood from untreated chronic HBV patients was used to analyze phenotypic markers, as well as cytokine production and cytoxicity of NK cells...
January 13, 2017: Antiviral Research
https://www.readbyqxmd.com/read/28088354/uncovering-oxysterol-binding-protein-osbp-as-a-target-of-the-anti-enteroviral-compound-ttp-8307
#4
Lucian Albulescu, Joëlle Bigay, Bishyajit Biswas, Marion Weber-Boyvat, Cristina M Dorobantu, Leen Delang, Hilde M van der Schaar, Young-Sik Jung, Johan Neyts, Vesa M Olkkonen, Frank J M van Kuppeveld, Jeroen R P M Strating
The genus Enterovirus (e.g. poliovirus, coxsackievirus, rhinovirus) of the Picornaviridae family of positive-strand RNA viruses includes many important pathogens linked to a range of acute and chronic diseases for which no approved antiviral therapy is available. Targeting a step in the life cycle that is highly conserved provides an attractive strategy for developing broad-range inhibitors of enterovirus infection. A step that is currently explored as a target for the development of antivirals is the formation of replication organelles, which support replication of the viral genome...
January 11, 2017: Antiviral Research
https://www.readbyqxmd.com/read/28087313/an-m2-v27a-channel-blocker-demonstrates-potent-in-vitro-and-in-vivo-antiviral-activities-against-amantadine-sensitive-and-resistant-influenza-a-viruses
#5
Yanmei Hu, Rami Musharrafieh, Chunlong Ma, Jiantao Zhang, Donald F Smee, William F DeGrado, Jun Wang
Adamantanes such as amantadine (1) and rimantadine (2) are FDA-approved anti-influenza drugs that act by inhibiting the wild-type M2 proton channel from influenza A viruses, thereby inhibiting the uncoating of the virus. Although adamantanes have been successfully used for more than four decades, their efficacy was curtailed by emerging drug resistance. Among the limited number of M2 mutants that confer amantadine resistance, the M2-V27A mutant was found to be the predominant mutant under drug selection pressure, thereby representing a high profile antiviral drug target...
January 10, 2017: Antiviral Research
https://www.readbyqxmd.com/read/28077314/biological-or-pharmacological-activation-of-protein-kinase-c-alpha-constrains-hepatitis-e-virus-replication
#6
Wenshi Wang, Yijin Wang, Yannick Debing, Xinying Zhou, Yuebang Yin, Lei Xu, Elena Herrera Carrillo, Johannes H Brandsma, Raymond A Poot, Ben Berkhout, Johan Neyts, Maikel P Peppelenbosch, Qiuwei Pan
Although hepatitis E has emerged as a global health issue, there is limited knowledge of its infection biology and no FDA-approved medication is available. Aiming to investigate the role of protein kinases in hepatitis E virus (HEV) infection and to identify potential antiviral targets, we screened a library of pharmacological kinase inhibitors in a cell culture model, a subgenomic HEV replicon containing luciferase reporter. We identified protein kinase C alpha (PKCα) as an essential cell host factor restricting HEV replication...
January 8, 2017: Antiviral Research
https://www.readbyqxmd.com/read/28063995/activation-of-tnf-%C3%AE-aid-axis-and-co-inhibitory-signals-in-coordination-with-th1-type-immunity-in-a-mouse-model-recapitulating-hepatitis-b
#7
Tomonori Matsumoto, Ken Takahashi, Tadashi Inuzuka, Soo Ki Kim, Tomoaki Kurosaki, Shigeru Kawakami, Tsutomu Chiba, Hiroshi Seno, Hiroyuki Marusawa
Hepatitis B virus (HBV) infection evokes host immune responses that primarily determine the outcome of HBV infection and the clinical features of HBV-associated liver disease. The precise mechanisms by which host factors restrict HBV replication, however, are poorly understood due to the lack of useful animal models that recapitulate immune responses to HBV. Here, we performed comprehensive immunologic gene expression profiling of the liver of a mouse model recapitulating anti-HBV immune response using a high sensitivity direct digital counting system...
January 5, 2017: Antiviral Research
https://www.readbyqxmd.com/read/28063994/heparin-prevents-zika-virus-induced-cytopathic-effects-in-human-neural-progenitor-cells
#8
Silvia Ghezzi, Lynsay Cooper, Alicia Rubio, Isabel Pagani, Maria Rosaria Capobianchi, Giuseppe Ippolito, Julien Pelletier, Maria Cecilia Z Meneghetti, Marcelo A Lima, Mark A Skidmore, Vania Broccoli, Edwin A Yates, Elisa Vicenzi
The recent Zika virus (ZIKV) outbreak, which mainly affected Brazil and neighbouring states, demonstrated the paucity of information concerning the epidemiology of several flaviruses, but also highlighted the lack of available agents with which to treat such emerging diseases. Here, we show that heparin, a widely used anticoagulant, while exerting a modest inhibitory effect on Zika Virus replication, fully prevents virus-induced cell death of human neural progenitor cells (NPCs).
January 5, 2017: Antiviral Research
https://www.readbyqxmd.com/read/28063996/porcine-parvovirus-capsid-protein-expressed-in-escherichia-coli-self-assembles-into-virus-like-particles-with-high-immunogenicity-in-mice-and-guinea-pigs
#9
Pengchao Ji, Yunchao Liu, Yumei Chen, Aiping Wang, Dawei Jiang, Baolei Zhao, Jvcai Wang, Shujun Chai, Enmin Zhou, Gaiping Zhang
Porcine parvovirus (PPV) is a causative agent of reproductive failure in pregnant sows. Classical inactivated vaccine is extensively used to control PPV infection, but problems concerning safety, such as incomplete inactivation may occur. In this study, a novel subunit vaccine against PPV based on virus-like particles (VLPs) formed from the complete PPV VP2 protein expressed in a prokaryotic system with co-expressed chaperones is reported. The VLPs have a similar size, shape, and hemagglutination property to the PPV...
January 4, 2017: Antiviral Research
https://www.readbyqxmd.com/read/28063993/inhibition-of-enterovirus-71-replication-by-an-%C3%AE-hydroxy-nitrile-derivative-nk-1-9k
#10
Yaxin Wang, Lin Cao, Yangyang Zhai, Jiaming Ma, Quandeng Nie, Ting Li, Zheng Yin, Yuna Sun, Luqing Shang
Enterovirus 71 (EV71) is one of the major etiological agents of human hand-foot-and-mouth disease (HFMD) worldwide. EV71 infection in young children and people with immunodeficiency causes severe symptoms with a high fatality rates. However, there is still no approved drugs to treat such infections. Based on our previous report of a peptide-aldehyde anti-EV71 protease, we present here a highly specific α-hydroxy-nitrile derivative NK-1.9k, which inhibited the proliferation of multiple EV71 strains and coxsackievirus A16 (CVA16) in various cells with EC50 of 37...
January 4, 2017: Antiviral Research
https://www.readbyqxmd.com/read/28062191/tracking-hcv-protease-population-diversity-during-transmission-and-susceptibility-of-founder-populations-to-antiviral-therapy
#11
Tanvi Khera, Daniel Todt, Koen Vercauteren, C Patrick McClure, Lieven Verhoye, Ali Farhoudi, Sabin Bhuju, Robert Geffers, Thomas F Baumert, Eike Steinmann, Philip Meuleman, Thomas Pietschmann, Richard J P Brown
Due to the highly restricted species-tropism of Hepatitis C virus (HCV) a limited number of animal models exist for pre-clinical evaluation of vaccines and antiviral compounds. The human-liver chimeric mouse model allows heterologous challenge with clinically relevant strains derived from patients. However, to date, the transmission and longitudinal evolution of founder viral populations in this model have not been characterized in-depth using state-of-the-art sequencing technologies. Focusing on NS3 protease encoding region of the viral genome, mutant spectra in a donor inoculum and individual recipient mice were determined via Illumina sequencing and compared, to determine the effects of transmission on founder viral population complexity...
January 3, 2017: Antiviral Research
https://www.readbyqxmd.com/read/28049006/obatoclax-saliphenylhalamide-and-gemcitabine-inhibit-zika-virus-infection-in%C3%A2-vitro-and-differentially-affect-cellular-signaling-transcription-and-metabolism
#12
Suvi Kuivanen, Maxim M Bespalov, Jatin Nandania, Aleksandr Ianevski, Vidya Velagapudi, Jef K De Brabander, Denis E Kainov, Olli Vapalahti
An epidemic of Zika virus (ZIKV) infection associated with congenital abnormalities such as microcephaly, is ongoing in the Americas and the Pacific. Currently there are no approved therapies to treat this emerging viral disease. Here, we tested three cell-directed broad-spectrum antiviral compounds against ZIKV replication using human retinal pigment epithelial (RPE) cells and a low-passage ZIKV strain isolated from fetal brain. We found that obatoclax, SaliPhe, and gemcitabine inhibited ZIKV infections at noncytotoxic concentrations...
December 31, 2016: Antiviral Research
https://www.readbyqxmd.com/read/28041959/substrate-selectivity-of-dengue-and-zika-virus-ns5-polymerase-towards-2-modified-nucleotide-analogues
#13
Supanee Potisopon, François Ferron, Véronique Fattorini, Barbara Selisko, Bruno Canard
In targeting the essential viral RNA-dependent RNA-polymerase (RdRp), nucleotide analogues play a major role in antiviral therapies. In the Flaviviridae family, the hepatitis C virus (HCV) can be eradicated from chronically infected patients using a combination of drugs which generally include the 2'-modified uridine analogue Sofosbuvir, delivered as nucleotide prodrug. Dengue and Zika viruses are emerging flaviviruses whose RdRp is closely related to that of HCV, yet no nucleoside drug has been clinically approved for these acute infections...
December 29, 2016: Antiviral Research
https://www.readbyqxmd.com/read/28040513/novel-chimeric-virus-like-particles-vaccine-displaying-mers-cov-receptor-binding-domain-induce-specific-humoral-and-cellular-immune-response-in-mice
#14
Chong Wang, Xuexing Zheng, Weiwei Gai, Gary Wong, Hualei Wang, Hongli Jin, Na Feng, Yongkun Zhao, Weijiao Zhang, Nan Li, Guoxing Zhao, Junfu Li, Jinghua Yan, Yuwei Gao, Guixue Hu, Songtao Yang, Xianzhu Xia
Middle East respiratory syndrome coronavirus (MERS-CoV) has continued spreading since its emergence in 2012 with a mortality rate of 35.6%, and is a potential pandemic threat. Prophylactics and therapies are urgently needed to address this public health problem. We report here the efficacy of a vaccine consisting of chimeric virus-like particles (VLP) expressing the receptor binding domain (RBD) of MERS-CoV. In this study, a fusion of the canine parvovirus (CPV) VP2 structural protein gene with the RBD of MERS-CoV can self-assemble into chimeric, spherical VLP (sVLP)...
December 28, 2016: Antiviral Research
https://www.readbyqxmd.com/read/28039021/buccal-viral-dna-as-a-trigger-for-brincidofovir-therapy-in-the-mousepox-model-of-smallpox
#15
Ryan Crump, Maria Korom, R Mark Buller, Scott Parker
Orthopoxviruses continue to pose a significant threat to the population as potential agents of bioterrorism. An intentional release of natural or engineered variola virus (VARV) or monkeypox viruses would cause mortality and morbidity in the target population. To address this, antivirals have been developed and evaluated in animal models of smallpox and monkeypox. One such antiviral, brincidofovir (BCV, previously CMX001), has demonstrated high levels of efficacy against orthopoxviruses in animal models and is currently under clinical evaluation for prevention and treatment of diseases caused by cytomegaloviruses and adenoviruses...
December 27, 2016: Antiviral Research
https://www.readbyqxmd.com/read/28039020/protein-kinases-c-as-potential-host-targets-for-the-inhibition-of-chikungunya-virus-replication
#16
Rana Abdelnabi, Siti Naqiah Amrun, Lisa F P Ng, Pieter Leyssen, Johan Neyts, Leen Delang
We have shown previously that prostratin, a non-tumor promoting phorbol ester, inhibits chikungunya virus (CHIKV)-induced cytopathic effects in vitro. Prostratin is a potent activator of protein kinases C (PKC), a family of related serine/threonine kinases that regulate many cellular processes such as proliferation and apoptosis. The objective of this study was to explore the mechanism of the anti-CHIKV activity of prostratin. Prostratin reduced the production of infectious virus particles and viral protein accumulation in a dose-dependent manner at a post-entry step during virus replication...
December 27, 2016: Antiviral Research
https://www.readbyqxmd.com/read/28034744/extended-substrate-specificity-and-first-potent-irreversible-inhibitor-activity-based-probe-design-for-zika-virus-ns2b-ns3-protease
#17
Wioletta Rut, Linlin Zhang, Paulina Kasperkiewicz, Marcin Poreba, Rolf Hilgenfeld, Marcin Drąg
Zika virus is spread by Aedes mosquitoes and is linked to acute neurological disorders, especially to microcephaly in newborn children and Guillan-Barré Syndrome. The NS2B-NS3 protease of this virus is responsible for polyprotein processing and therefore considered an attractive drug target. In this study, we have used the Hybrid Combinatorial Substrate Library (HyCoSuL) approach to determine the substrate specificity of ZIKV NS2B-NS3 protease in the P4-P1 positions using natural and a large spectrum of unnatural amino acids...
December 26, 2016: Antiviral Research
https://www.readbyqxmd.com/read/28034743/discovery-of-host-targeted-covalent-inhibitors-of-dengue-virus
#18
Mélissanne de Wispelaere, Margot Carocci, Yanke Liang, Qingsong Liu, Eileen Sun, Michael L Vetter, Jinhua Wang, Nathanael S Gray, Priscilla L Yang
We report here on an approach targeting the host reactive cysteinome to identify inhibitors of host factors required for the infectious cycle of Flaviviruses and other viruses. We used cellular phenotypic screens to identify a series of covalent inhibitors, exemplified by QL-XII-47, that are active against dengue virus. We demonstrate that the compounds effectively block viral protein expression. This inhibition is associated with repression of downstream processes of the infectious cycle, and thus significantly contributes to the potent antiviral activity of these compounds...
December 26, 2016: Antiviral Research
https://www.readbyqxmd.com/read/28034742/activity-of-andrographolide-against-dengue-virus
#19
Patcharee Panraksa, Suwipa Ramphan, Sarawut Khongwichit, Duncan R Smith
Dengue is the most prevalent arthropod-transmitted viral illness of humans, with an estimated 100 million symptomatic infections occurring each year and more than 2.5 billion people living at risk of infection. There are no approved antiviral agents against dengue virus, and there is only limited introduction of a dengue vaccine in some countries. Andrographolide is derived from Andrographis paniculata, a medicinal plant traditionally used to treat a number of conditions including infections. The antiviral activity of andrographolide against dengue virus (DENV) serotype 2 was evaluated in two cell lines (HepG2 and HeLa) while the activity against DENV 4 was evaluated in one cell line (HepG2)...
December 26, 2016: Antiviral Research
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...
December 26, 2016: Antiviral Research
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