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https://www.readbyqxmd.com/read/29879523/enhancing-preparation-for-large-nipah-outbreaks-beyond-bangladesh-preventing-a-tragedy-like-ebola-in-west-africa
#1
Halsie Donaldson, Daniel Lucey
The Nipah virus has been reported to be transmitted from person-to-person following close contact in non-urban parts of India (including Kerala as of May 2018),Bangladesh, and the Philippines. It can cause encephalitis and pneumonia, and has a high case fatality rate. Nipah is a prime example of a One Health zoonotic emerging and reemerging infectious disease with consistent links to fruit bats, and sometimes pigs or horses. We argue for anticipating larger rural, and urban, outbreaks of Nipah, and preparing for them by accelerating development and testing of countermeasures: antiviral drugs,immunotherapeutic antibodies, vaccines, rapid diagnostics, personal protective equipment(PPE) for health workers and online WHO training by experts from Bangladesh, India and elsewhere...
June 4, 2018: International Journal of Infectious Diseases: IJID
https://www.readbyqxmd.com/read/29874821/1-benzyl-3-cetyl-2-methylimidazolium-iodide-nh125-is-a-broad-spectrum-inhibitor-of-virus-entry-with-lysosomotropic-features
#2
Sarah Moeschler, Samira Locher, Gert Zimmer
Cellular kinases are crucial for the transcription/replication of many negative-strand RNA viruses and might serve as targets for antiviral therapy. In this study, a library comprising 80 kinase inhibitors was screened for antiviral activity against vesicular stomatitis virus (VSV), a prototype member of the family Rhabdoviridae . 1-Benzyl-3-cetyl-2-methylimidazolium iodide (NH125), an inhibitor of eukaryotic elongation factor 2 (eEF2) kinase, significantly inhibited entry of single-cycle VSV encoding a luciferase reporter...
June 5, 2018: Viruses
https://www.readbyqxmd.com/read/29870771/identification-of-a-small-molecule-inhibitor-of-ebolavirus-genome-replication-and-transcription-using-in-silico-screening
#3
Victoria Easton, Martin McPhillie, Isabel Garcia-Dorival, John Barr, Thomas Edwards, Richard Foster, Colin Fishwick, Mark Harris
Ebola virus (EBOV) causes a severe haemorrhagic fever in humans and has a mortality rate over 50%. With no licensed drug treatments available, EBOV poses a significant threat. Investigations into possible therapeutics have been severely hampered by the classification of EBOV as a BSL4 pathogen. Here, we describe a drug discovery pathway combining in silico screening of compounds predicted to bind to a hydrophobic pocket on the nucleoprotein (NP); with a robust and rapid EBOV minigenome assay for inhibitor validation at BSL2...
June 2, 2018: Antiviral Research
https://www.readbyqxmd.com/read/29860496/development-of-clinical-stage-human-monoclonal-antibodies-that-treat-advanced-ebola-virus-disease-in-non-human-primates
#4
Kristen E Pascal, Drew Dudgeon, John C Trefry, Manu Anantpadma, Yasuteru Sakurai, Charles D Murin, Hannah L Turner, Jeanette Fairhurst, Marcela Torres, Ashique Rafique, Ying Yan, Ashok Badithe, Kevin Yu, Terra Potocky, Sandra L Bixler, Taylor B Chance, William D Pratt, Franco D Rossi, Joshua D Shamblin, Suzanne E Wollen, Justine M Zelko, Ricardo Carrion, Gabriella Worwa, Hilary M Staples, Darya Burakov, Robert Babb, Gang Chen, Joel Martin, Tammy T Huang, Karl Erlandson, Melissa S Willis, Kimberly Armstrong, Thomas M Dreier, Andrew B Ward, Robert A Davey, Margaret L M Pitt, Leah Lipsich, Peter Mason, William Olson, Neil Stahl, Christos A Kyratsous
Background: For most classes of drugs rapid development of therapeutics to treat emerging infections is challenged by the timelines needed to identify compounds with the desired efficacy, safety and PK profiles. Fully human monoclonal antibodies (mAbs) provide an attractive method to overcome many of these hurdles to rapidly produce therapeutics for emerging diseases. Methods: Here we deployed a platform to generate, test and develop fully human antibodies to Zaire ebolavirus...
May 31, 2018: Journal of Infectious Diseases
https://www.readbyqxmd.com/read/29789732/experimental-drugs-poised-for-use-in-ebola-outbreak
#5
Erika Check Hayden
No abstract text is available yet for this article.
May 2018: Nature
https://www.readbyqxmd.com/read/29746898/two-pore-channels-and-disease
#6
REVIEW
Sandip Patel, Bethan S Kilpatrick
Two-pore channels (TPCs) are Ca2+ -permeable endo-lysosomal ion channels subject to multi-modal regulation. They mediate their physiological effects through releasing Ca2+ from acidic organelles in response to cues such as the second messenger, NAADP. Here, we review emerging evidence linking TPCs to disease. We discuss how perturbing both local and global Ca2+ changes mediated by TPCs through chemical and/or molecular manipulations can induce or reverse disease phenotypes. We cover evidence from models of Parkinson's disease, non-alcoholic fatty liver disease, Ebola infection, cancer, cardiac dysfunction and diabetes...
May 7, 2018: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/29741894/structures-of-ebolavirus-glycoprotein-complexes-with-tricyclic-antidepressant-and-antipsychotic-drugs
#7
Yuguang Zhao, Jingshan Ren, Elizabeth Evelyn Fry, Julia Xiao, Alain R Townsend, David I Stuart
A large number of Food and Drug Administration (FDA) approved drugs have been found to inhibit cell entry of Ebola virus (EBOV). However, since these drugs have various primary pharmacological targets their mechanisms of action against EBOV remain largely unknown. We have previously shown that six FDA approved drugs inhibit EBOV infection by interacting with and destabilizing the viral glycoprotein (GP). Here we show that the antidepressants imipramine and clomipramine, and antipsychotic drug thioridazine also directly interact with EBOV GP, and determine the mode of interaction by crystallographic analysis of the complexes...
May 9, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29723168/malaria-surveillance-united-states-2015
#8
Kimberly E Mace, Paul M Arguin, Kathrine R Tan
PROBLEM/CONDITION: Malaria in humans is caused by intraerythrocytic protozoa of the genus Plasmodium. These parasites are transmitted by the bite of an infective female Anopheles species mosquito. The majority of malaria infections in the United States occur among persons who have traveled to regions with ongoing malaria transmission. However, malaria is occasionally acquired by persons who have not traveled out of the country through exposure to infected blood products, congenital transmission, laboratory exposure, or local mosquitoborne transmission...
May 4, 2018: MMWR. Surveillance Summaries: Morbidity and Mortality Weekly Report. Surveillance Summaries
https://www.readbyqxmd.com/read/29719780/establishment-of-pseudovirus-infection-mouse-models-for-in-vivo-pharmacodynamics-evaluation-of-filovirus-entry-inhibitors
#9
Qing Chen, Ke Tang, Xiaoyu Zhang, Panpan Chen, Ying Guo
Filoviruses cause severe and fatal viral hemorrhagic fever in humans. Filovirus research has been extensive since the 2014 Ebola outbreak. Due to their high pathogenicity and mortality, live filoviruses require Biosafety Level-4 (BSL-4) facilities, which have restricted the development of anti-filovirus vaccines and drugs. An HIV-based pseudovirus cell infection assay is widely used for viral entry studies in BSL-2 conditions. Here, we successfully constructed nine in vitro pseudo-filovirus models covering all filovirus genera and three in vivo pseudo-filovirus-infection mouse models using Ebola virus, Marburg virus, and Lloviu virus as representative viruses...
March 2018: Acta Pharmaceutica Sinica. B
https://www.readbyqxmd.com/read/29717011/statins-suppress-ebola-virus-infectivity-by-interfering-with-glycoprotein-processing
#10
Punya Shrivastava-Ranjan, Mike Flint, Éric Bergeron, Anita K McElroy, Payel Chatterjee, César G Albariño, Stuart T Nichol, Christina F Spiropoulou
Ebola virus (EBOV) infection is a major public health concern due to high fatality rates and limited effective treatments. Statins, widely used cholesterol-lowering drugs, have pleiotropic mechanisms of action and were suggested as potential adjunct therapy for Ebola virus disease (EVD) during the 2013-2016 outbreak in West Africa. Here, we evaluated the antiviral effects of statin (lovastatin) on EBOV infection in vitro Statin treatment decreased infectious EBOV production in primary human monocyte-derived macrophages and in the hepatic cell line Huh7...
May 1, 2018: MBio
https://www.readbyqxmd.com/read/29624387/computer-aided-discovery-and-characterization-of-novel-ebola-virus-inhibitors
#11
Stephen J Capuzzi, Wei Sun, Eugene N Muratov, Carles Martínez-Romero, Shihua He, Wenjun Zhu, Hao Li, Gregory Tawa, Ethan G Fisher, Miao Xu, Paul Shinn, Xiangguo Qiu, Adolfo García-Sastre, Wei Zheng, Alexander Tropsha
The Ebola virus (EBOV) causes severe human infection that lacks effective treatment. A recent screen identified a series of compounds that block EBOV-like particle entry into human cells. Using data from this screen, quantitative structure-activity relationship models were built and employed for virtual screening of a ∼17 million compound library. Experimental testing of 102 hits yielded 14 compounds with IC50 values under 10 μM, including several sub-micromolar inhibitors, and more than 10-fold selectivity against host cytotoxicity...
April 26, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29606141/-researchers-have-love-for-life-opportunities-and-barriers-to-engage-pregnant-women-in-malaria-research-in-post-ebola-liberia
#12
Guillermo Martínez Pérez, Christine K Tarr-Attia, Bondey Breeze-Barry, Adelaida Sarukhan, Dawoh Peter Lansana, Ana Meyer García-Sípido, Anna Rosés, María Maixenchs, Quique Bassat, Alfredo Mayor
BACKGROUND: Adoption of prevention and therapeutic innovations to ensure that National Malaria Control Programmes meet their incidence reduction targets is highly dependent on the conduct of rigorous clinical trials. In Liberia, malaria control virtually halted during the recent Ebola epidemic, and could enormously benefit from innovations to protect its most vulnerable populations, including pregnant women, against malaria. Health policy-planners could feel more inclined to adopt novel interventions with demonstrated safety and efficacy when trialled among their women population...
April 2, 2018: Malaria Journal
https://www.readbyqxmd.com/read/29584730/antiviral-efficacy-of-favipiravir-against-ebola-virus-a-translational-study-in-cynomolgus-macaques
#13
Jérémie Guedj, Géraldine Piorkowski, Frédéric Jacquot, Vincent Madelain, Thi Huyen Tram Nguyen, Anne Rodallec, Stephan Gunther, Caroline Carbonnelle, France Mentré, Hervé Raoul, Xavier de Lamballerie
BACKGROUND: Despite repeated outbreaks, in particular the devastating 2014-2016 epidemic, there is no effective treatment validated for patients with Ebola virus disease (EVD). Among the drug candidates is the broad-spectrum polymerase inhibitor favipiravir, which showed a good tolerance profile in patients with EVD (JIKI trial) but did not demonstrate a strong antiviral efficacy. In order to gain new insights into the antiviral efficacy of favipiravir and improve preparedness and public health management of future outbreaks, we assess the efficacy achieved by ascending doses of favipiravir in Ebola-virus-infected nonhuman primates (NHPs)...
March 2018: PLoS Medicine
https://www.readbyqxmd.com/read/29568066/human-transbodies-that-interfere-with-the-functions-of-ebola-virus-vp35-protein-in-genome-replication-and-transcription-and-innate-immune-antagonism
#14
Watee Seesuay, Surasak Jittavisutthikul, Nawannaporn Sae-Lim, Nitat Sookrung, Yuwaporn Sakolvaree, Wanpen Chaicumpa
Small molecular inhibitors and passive immunization against Ebola virus disease (EVD) have been tested in animal models, including rodents and non-human primates, as well as in clinical trials. Nevertheless, there is currently no Food and Drug Administration (FDA)-approved therapy, and alternative strategies must be pursued. The aim of this study was to produce cell-penetrable human single-chain antibodies (transbodies) that are able to interfere with the activities of interferon inhibitory domain (IID) of the VP35 protein, a multifunctional virulence factor of Ebola virus (EBOV)...
March 21, 2018: Emerging Microbes & Infections
https://www.readbyqxmd.com/read/29566079/testing-therapeutics-in-cell-based-assays-factors-that-influence-the-apparent-potency-of-drugs
#15
Elena Postnikova, Yu Cong, Lisa Evans DeWald, Julie Dyall, Shuiqing Yu, Brit J Hart, Huanying Zhou, Robin Gross, James Logue, Yingyun Cai, Nicole Deiuliis, Julia Michelotti, Anna N Honko, Richard S Bennett, Michael R Holbrook, Gene G Olinger, Lisa E Hensley, Peter B Jahrling
Identifying effective antivirals for treating Ebola virus disease (EVD) and minimizing transmission of such disease is critical. A variety of cell-based assays have been developed for evaluating compounds for activity against Ebola virus. However, very few reports discuss the variable assay conditions that can affect the results obtained from these drug screens. Here, we describe variable conditions tested during the development of our cell-based drug screen assays designed to identify compounds with anti-Ebola virus activity using established cell lines and human primary cells...
2018: PloS One
https://www.readbyqxmd.com/read/29559198/new-phenylaniline-derivatives-as-modulators-of-amyloid-protein-precursor-metabolism
#16
Marion Gay, Pascal Carato, Mathilde Coevoet, Nicolas Renault, Paul-Emmanuel Larchanché, Amélie Barczyk, Saïd Yous, Luc Buée, Nicolas Sergeant, Patricia Melnyk
The chloroquinoline scaffold is characteristic of anti-malarial drugs such as chloroquine (CQ) or amodiaquine (AQ). These drugs are also described for their potential effectiveness against prion disease, HCV, EBV, Ebola virus, cancer, Parkinson or Alzheimer diseases. Amyloid precursor protein (APP) metabolism is deregulated in Alzheimer's disease. Indeed, CQ modifies amyloid precursor protein (APP) metabolism by precluding the release of amyloid-beta peptides (Aβ), which accumulate in the brain of Alzheimer patients to form the so-called amyloid plaques...
May 1, 2018: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/29534607/addressing-the-selectivity-and-toxicity-of-antiviral-nucleosides
#17
Joy Y Feng
Nucleoside and nucleotide analogs have played significant roles in antiviral therapies and are valued for their impressive potency and high barrier to resistance. They have been approved for treatment of herpes simplex virus-1, HIV, HBV, HCV, and influenza, and new drugs are being developed for the treatment of RSV, Ebola, coronavirus MERS, and other emerging viruses. However, this class of compounds has also experienced a high attrition rate in clinical trials due to toxicity. In this review, we discuss the utility of different biochemical and cell-based assays and provide recommendations for assessing toxicity liability before entering animal toxicity studies...
January 2018: Antiviral Chemistry & Chemotherapy
https://www.readbyqxmd.com/read/29524445/favipiravir-as-a-potential-countermeasure-against-neglected-and-emerging-rna-viruses
#18
REVIEW
Leen Delang, Rana Abdelnabi, Johan Neyts
Favipiravir, also known as T-705, is an antiviral drug that has been approved in 2014 in Japan to treat pandemic influenza virus infections. The drug is converted intracellularly into its active, phosphoribosylated form, which is recognized as a substrate by the viral RNA-dependent RNA polymerase. Interestingly, besides its anti-influenza virus activity, this molecule is also able to inhibit the replication of flavi-, alpha-, filo-, bunya-, arena-, noro-, and of other RNA viruses, which include neglected and (re)emerging viruses for which no antiviral therapy is currently available...
May 2018: Antiviral Research
https://www.readbyqxmd.com/read/29507309/recombinant-rna-dependent-rna-polymerase-complex-of-ebola-virus
#19
Egor P Tchesnokov, Parisa Raeisimakiani, Marianne Ngure, David Marchant, Matthias Götte
Here we report on the expression, purification and characterization of recombinant ebola virus RNA-dependent RNA polymerase (EBOV RdRp). Active protein complexes composed of the large L protein and viral protein VP35 were isolated from insect cells and analyzed using a short primer/template substrate that allowed benchmarking against related enzymes. RNA synthesis by multiprotein complexes of EBOV, influenza B, respiratory syncytial virus (RSV) and monomeric enzymes of hepatitis C and Zika (ZIKV) viruses required a 5'-phosporylated primer...
March 5, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29498743/amiodarone-affects-ebola-virus-binding-and-entry-into-target-cells
#20
Cristiano Salata, Denis Munegato, Francesco Martelli, Cristina Parolin, Arianna Calistri, Aldo Baritussio, Giorgio Palù
Ebola Virus Disease is one of the most lethal transmissible infections characterized by a high fatality rate. Several research studies have aimed to identify effective antiviral agents. Amiodarone, a drug used for the treatment of arrhythmias, has been shown to inhibit filovirus infection in vitro by acting at the early step of the viral replication cycle. Here we demonstrate that amiodarone reduces virus binding to target cells and slows down the progression of the viral particles along the endocytic pathway...
March 2, 2018: New Microbiologica
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