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https://www.readbyqxmd.com/read/29624387/computer-aided-discovery-and-characterization-of-novel-ebola-virus-inhibitors
#1
Stephen Joseph Capuzzi, Wei Sun, Eugene N Muratov, Carles Martinez-Romero, Shihua He, Wenjun Zhu, Hao Li, Gregory James 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 (QSAR) 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 6, 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
#2
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
#3
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
#4
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
#5
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
#6
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...
March 12, 2018: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/29534607/addressing-the-selectivity-and-toxicity-of-antiviral-nucleosides
#7
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
#8
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...
March 7, 2018: Antiviral Research
https://www.readbyqxmd.com/read/29507309/recombinant-rna-dependent-rna-polymerase-complex-of-ebola-virus
#9
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
#10
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
https://www.readbyqxmd.com/read/29495311/development-and-validation-of-a-novel-dual-luciferase-reporter-gene-assay-to-quantify-ebola-virus-vp24-inhibition-of-ifn-signaling
#11
Elisa Fanunza, Aldo Frau, Marco Sgarbanti, Roberto Orsatti, Angela Corona, Enzo Tramontano
The interferon (IFN) system is the first line of defense against viral infections. Evasion of IFN signaling by Ebola viral protein 24 (VP24) is a critical event in the pathogenesis of the infection and, hence, VP24 is a potential target for drug development. Since no drugs target VP24, the identification of molecules able to inhibit VP24, restoring and possibly enhancing the IFN response, is a goal of concern. Accordingly, we developed a dual signal firefly and Renilla luciferase cell-based drug screening assay able to quantify IFN-mediated induction of Interferon Stimulated Genes (ISGs) and its inhibition by VP24...
February 24, 2018: Viruses
https://www.readbyqxmd.com/read/29489836/the-ebola-effect-in-guinea-2014-15-tangled-trends-of-malaria-care-in-children-under-five
#12
Delphin Kolie, Bienvenu S Camara, Alexandre Delamou, Abdoul H Béavogui, Veerle Hermans, Jeffrey K Edwards, Guido Benedetti, Claude P Muller, Johan van Griensven, Rony Zachariah
INTRODUCTION: The 2014-15 Ebola outbreak in West Africa was disruptive for the general health services in the affected countries. This study assessed the impact of the outbreak on the reported number and management of malaria in children under-five in rural Guinea. MATERIALS AND METHODS: A retrospective cross-sectional study was conducted in nineteen health centres in two rural, malaria-endemic health districts, one at the epicentre of the outbreak (Guéckédou) and one (Koubia) spared by Ebola...
2018: PloS One
https://www.readbyqxmd.com/read/29457711/small-animal-models-for-evaluating-filovirus-countermeasures
#13
Logan Banadyga, Gary Wong, Xiangguo Qiu
The development of novel therapeutics and vaccines to treat or prevent disease caused by filoviruses, such as Ebola and Marburg viruses, depends on the availability of animal models that faithfully recapitulate clinical hallmarks of disease as it is observed in humans. In particular, small animal models (like mice and guinea pigs) are historically and frequently used for the primary evaluation of antiviral countermeasures, prior to testing in nonhuman primates, which represent the gold-standard filovirus animal model...
February 19, 2018: ACS Infectious Diseases
https://www.readbyqxmd.com/read/29452047/lessons-learned-from-ebola-vaccine-r-d-during-a-public-health-emergency
#14
Marie-Paule Kieny
In spite of a complete lack of Research and Development (R&D) preparedness, the 2013-2016 West-Africa Ebola experience demonstrated that it is possible to compress R&D timelines to less than a single year, from a more usual decade or longer. This is mostly to be credited to an unprecedented collaborative effort building on the availability of a small number of candidate diagnostic tests, drugs and vaccines that could be moved rapidly into the clinical phase evaluation. The World Health Organization (WHO) led international consultations and activities - including the organization of a successful Ebola vaccine efficacy trial in Guinea - as a contribution to the unprecedented global efforts to control the Ebola epidemic...
February 16, 2018: Human Vaccines & Immunotherapeutics
https://www.readbyqxmd.com/read/29428508/the-molecular-tweezer-clr01-inhibits-ebola-and-zika-virus-infection
#15
Annika E Röcker, Janis A Müller, Erik Dietzel, Mirja Harms, Franziska Krüger, Christian Heid, Andrea Sowislok, Camilla Frich Riber, Alexandra Kupke, Sina Lippold, Jens von Einem, Judith Beer, Bernd Knöll, Stephan Becker, Jonas Schmidt-Chanasit, Markus Otto, Olli Vapalahti, Alexander N Zelikin, Gal Bitan, Thomas Schrader, Jan Münch
Ebola (EBOV) and Zika viruses (ZIKV) are responsible for recent global health threats. As no preventive vaccines or antiviral drugs against these two re-emerging pathogens are available, we evaluated whether the molecular tweezer CLR01 may inhibit EBOV and ZIKV infection. This small molecule previously has been shown to inactivate HIV-1 and herpes viruses through a selective interaction with lipid-raft-rich regions in the viral envelope, which results in membrane disruption and loss of infectivity. We found that CLR01 indeed blocked infection of EBOV and ZIKV in a dose-dependent manner...
February 8, 2018: Antiviral Research
https://www.readbyqxmd.com/read/29369776/successful-treatment-of-marburg-virus-with-orally-administrated-t-705-favipiravir-in-a-mouse-model
#16
Wenjun Zhu, Zirui Zhang, Shihua He, Gary Wong, Logan Banadyga, Xiangguo Qiu
Filoviruses, such as Marburg and Ebola viruses, cause severe disease in humans with high case fatality rates and are therefore considered biological threat agents. To date, no licensed vaccine or therapeutic exists for their treatment. T-705 (favipiravir) is a pyrazinecarboxamide derivative that has shown broad antiviral activity against a number of viruses and is clinically licenced in Japan to treat influenza. Here we report the efficacy of T-705 against Marburg virus infection in vitro and in vivo. Notably, oral administration of T-705 beginning one or two days post-infection and continuing for eight days resulted in complete survival of mice that had been intraperitoneally infected with mouse-adapted Marburg virus (variant Angola)...
March 2018: Antiviral Research
https://www.readbyqxmd.com/read/29361403/structure-based-virtual-screening-of-the-ebola-virus-trimeric-glycoprotein-using-consensus-scoring
#17
Abdulmujeeb T Onawole, Temitope U Kolapo, Kazeem O Sulaiman, Rukayat O Adegoke
Ebola virus (EBOV) causes zoonotic viral infection with a potential risk of global spread and a highly fatal effect on humans. Till date, no drug has gotten market approval for the treatment of Ebola virus disease (EVD), and this perhaps allows the use of both experimental and computational approaches in the antiviral drug discovery process. The main target of potential vaccines that are recently undergoing clinical trials is trimeric glycoprotein (GP) of the EBOV and its exact crystal structure was used in this structure based virtual screening study, with the aid of consensus scoring to select three possible hit compounds from about 36 million compounds in MCULE's database...
February 2018: Computational Biology and Chemistry
https://www.readbyqxmd.com/read/29305306/filovirus-proteins-for-antiviral-drug-discovery-structure-function-of-proteins-involved-in-assembly-and-budding
#18
REVIEW
Baptiste Martin, Olivier Reynard, Viktor Volchkov, Etienne Decroly
There are no approved medications for the treatment of Marburg or Ebola virus infection. In two previous articles (Martin et al., 2016, Martin et al., 2017), we reviewed surface glycoprotein and replication proteins structure/function relationship to decipher the molecular mechanisms of filovirus life cycle and identify antiviral strategies. In the present article, we recapitulate knowledge about the viral proteins involved in filovirus assembly and budding. First we describe the structural data available for viral proteins associated with virus assembly and virion egress and then, we integrate the structural features of these proteins in the functional context of the viral replication cycle...
February 2018: Antiviral Research
https://www.readbyqxmd.com/read/29297408/nubia-s-mother-being-pregnant-in-the-time-of-experimental-vaccines-and-therapeutics-for-ebola
#19
Séverine Caluwaerts
During the 2014-2016 Ebola epidemic, Médecins Sans Frontières (MSF) treated Ebola-positive pregnant women in its Ebola Treatment Centers (ETCs). For pregnant women with confirmed Ebola virus disease, inclusion in clinical vaccine/drug/therapeutic trials was complicated. Despite their extremely high Ebola-related mortality in previous epidemics (89-93%) and a neonatal mortality of 100%, theoretical concerns about safety of vaccines and therapeutics in pregnancy were invoked, limiting pregnant women's access to an experimental live attenuated vaccine and brincidofovir, an experimental antiviral...
December 14, 2017: Reproductive Health
https://www.readbyqxmd.com/read/29297366/protected-to-death-systematic-exclusion-of-pregnant-women-from-ebola-virus-disease-trials
#20
Melba F Gomes, Vânia de la Fuente-Núñez, Abha Saxena, Annette C Kuesel
BACKGROUND: For 30 years, women have sought equal opportunity to be included in trials so that drugs are equitably studied in women as well as men; regulatory guidelines have changed accordingly. Pregnant women, however, continue to be excluded from trials for non-obstetric conditions, though they have been included for trials of life-threatening diseases because prospects for maternal survival outweighed potential fetal risks. Ebola virus disease is a life-threatening infection without approved treatments or vaccines...
December 14, 2017: Reproductive Health
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