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https://www.readbyqxmd.com/read/28643204/host-factors-in-coronavirus-replication
#1
Adriaan H de Wilde, Eric J Snijder, Marjolein Kikkert, Martijn J van Hemert
Coronaviruses are pathogens with a serious impact on human and animal health. They mostly cause enteric or respiratory disease, which can be severe and life threatening, e.g., in the case of the zoonotic coronaviruses causing severe acute respiratory syndrome (SARS) and Middle East Respiratory Syndrome (MERS) in humans. Despite the economic and societal impact of such coronavirus infections, and the likelihood of future outbreaks of additional pathogenic coronaviruses, our options to prevent or treat coronavirus infections remain very limited...
June 23, 2017: Current Topics in Microbiology and Immunology
https://www.readbyqxmd.com/read/28642467/targeting-coronaviral-replication-and-cellular-jak2-mediated-dominant-nf-%C3%AE%C2%BAb-activation-for-comprehensive-and-ultimate-inhibition-of-coronaviral-activity
#2
Cheng-Wei Yang, Yue-Zhi Lee, Hsing-Yu Hsu, Chuan Shih, Yu-Sheng Chao, Hwan-You Chang, Shiow-Ju Lee
Tylophorine-based compounds exert broad spectral, potent inhibition of coronaviruses. NF-κB activation is a common pro-inflammatory response of host cells to viral infection. The aims of this study were to (i) find an effective combination treatment for coronaviral infections through targeting of the virus per se and cellular NF-κB activity; and (ii) to study the underling mechanisms. We found that tylophorine-based compounds target the TGEV viral RNA and effectively inhibit TGEV replication. NF-κB inhibition also leads to anti-TGEV replication...
June 22, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28636590/host-and-viral-traits-predict-zoonotic-spillover-from-mammals
#3
Kevin J Olival, Parviez R Hosseini, Carlos Zambrana-Torrelio, Noam Ross, Tiffany L Bogich, Peter Daszak
The majority of human emerging infectious diseases are zoonotic, with viruses that originate in wild mammals of particular concern (for example, HIV, Ebola and SARS). Understanding patterns of viral diversity in wildlife and determinants of successful cross-species transmission, or spillover, are therefore key goals for pandemic surveillance programs. However, few analytical tools exist to identify which host species are likely to harbour the next human virus, or which viruses can cross species boundaries. Here we conduct a comprehensive analysis of mammalian host-virus relationships and show that both the total number of viruses that infect a given species and the proportion likely to be zoonotic are predictable...
June 21, 2017: Nature
https://www.readbyqxmd.com/read/28633899/discovery-of-bms-961955-an-allosteric-inhibitor-of-the-hepatitis-c-virus-ns5b-polymerase
#4
Barbara Zhizhen Zheng, Stanley V D'Andrea, Umesh Hanumegowda, Jay O Knipe, Kathy Mosure, Xiaoliang Zhuo, Julie A Lemm, Mengping Liu, Karen L Rigat, Ying-Kai Wang, Hua Fang, Chris Poronsky, Jingfang Cutrone, Dauh-Rurng Wu, Pirama Nayagam Arunachalam, T J Balapragalathan, Arunachalam Arumugam, Arvind Mathur, Nicholas A Meanwell, Min Gao, Susan B Roberts, John F Kadow
The synthesis, structure-activity relationship (SAR) data, and further optimization of the metabolic stability and pharmacokinetic (PK) properties for a previously disclosed class of cyclopropyl-fused indolobenzazepine HCV NS5B polymerase inhibitors are described. These efforts led to the discovery of BMS-961955 as a viable contingency backup to beclabuvir which was recently approved in Japan for the treatment of HCV as part of a three drug, single pill combination marketed as Ximency(TM).
June 11, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28616501/searching-for-animal-models-and-potential-target-species-for-emerging-pathogens-experience-gained-from-middle-east-respiratory-syndrome-mers-coronavirus
#5
REVIEW
Júlia Vergara-Alert, Enric Vidal, Albert Bensaid, Joaquim Segalés
Emerging and re-emerging pathogens represent a substantial threat to public health, as demonstrated with numerous outbreaks over the past years, including the 2013-2016 outbreak of Ebola virus in western Africa. Coronaviruses are also a threat for humans, as evidenced in 2002/2003 with infection by the severe acute respiratory syndrome coronavirus (SARS-CoV), which caused more than 8000 human infections with 10% fatality rate in 37 countries. Ten years later, a novel human coronavirus (Middle East respiratory syndrome coronavirus, MERS-CoV), associated with severe pneumonia, arose in the Kingdom of Saudi Arabia...
June 2017: One Health
https://www.readbyqxmd.com/read/28600079/synthesis-antiviral-evaluation-and-molecular-docking-studies-of-n-4-aryl-substituted-unsubstituted-thiosemicarbazones-derived-from-1-indanones-as-potent-anti-bovine-viral-diarrhea-virus-agents
#6
María C Soraires Santacruz, Matías Fabiani, Eliana F Castro, Lucía V Cavallaro, Liliana M Finkielsztein
A series of N(4)-arylsubstituted thiosemicarbazones derived from 1-indanones and a set of compounds lacking such substitution in the N(4) position of the thiosemicarbazone moiety were synthesized and evaluated for their anti-bovine viral diarrhea virus (BVDV) activity. Among these, derivatives 2 and 15 displayed high activity (EC50=2.7±0.4 and 0.7±0.1µM, respectively) as inhibitors of BVDV replication. Novel key structural features related to the anti-BVDV activity were identified by structure-activity relationship (SAR) analysis...
May 27, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28596841/targeting-endosomal-acidification-by-chloroquine-analogs-as-a-promising-strategy-for-the-treatment-of-emerging-viral-diseases
#7
REVIEW
Md Abdul Alim Al-Bari
Emerging viruses such as HIV, dengue, influenza A, SARS coronavirus, Ebola, and other viruses pose a significant threat to human health. Majority of these viruses are responsible for the outbreaks of pathogenic lethal infections. To date, there are no effective therapeutic strategies available for the prophylaxis and treatment of these infections. Chloroquine analogs have been used for decades as the primary and most successful drugs against malaria. Concomitant with the emergence of chloroquine-resistant Plasmodium strains and a subsequent decrease in the use as antimalarial drugs, other applications of the analogs have been investigated...
February 2017: Pharmacology Research & Perspectives
https://www.readbyqxmd.com/read/28592648/allelic-variation-in-the-toll-like-receptor-adaptor-protein-ticam2-contributes-to-sars-coronavirus-pathogenesis-in-mice
#8
Lisa E Gralinski, Vineet D Menachery, Andrew P Morgan, Allison L Totura, Anne Beall, Jacob Kocher, Jessica Plante, D Corinne Harrison-Shostak, Alexandra Schäfer, Fernando Pardo-Manuel de Villena, Martin T Ferris, Ralph S Baric
Host genetic variation is known to contribute to differential pathogenesis following infection. Mouse models allow direct assessment of host genetic factors responsible for susceptibility to Severe Acute Respiratory Syndrome coronavirus (SARS-CoV). Based on an assessment of early stage lines from the Collaborative Cross mouse multi-parent population, we identified two lines showing highly divergent susceptibilities to SARS-CoV: the resistant CC003/Unc and the susceptible CC053/Unc. We generated 264 F2 mice between these strains, and infected them with SARS-CoV...
June 7, 2017: G3: Genes—Genomes—Genetics
https://www.readbyqxmd.com/read/28591694/the-nucleocapsid-proteins-of-mouse-hepatitis-virus-and-severe-acute-respiratory-syndrome-coronavirus-share-the-same-ifn-%C3%AE-antagonizing-mechanism-attenuation-of-pact-mediated-rig-i-mda5-activation
#9
Zhen Ding, Liurong Fang, Shuangling Yuan, Ling Zhao, Xunlei Wang, Siwen Long, Mohan Wang, Dang Wang, Mohamed Frahat Foda, Shaobo Xiao
Coronaviruses (CoVs) are a huge threat to both humans and animals and have evolved elaborate mechanisms to antagonize interferons (IFNs). Nucleocapsid (N) protein is the most abundant viral protein in CoV-infected cells, and has been identified as an innate immunity antagonist in several CoVs, including mouse hepatitis virus (MHV) and severe acute respiratory syndrome (SARS)-CoV. However, the underlying molecular mechanism(s) remain unclear. In this study, we found that MHV N protein inhibited Sendai virus and poly(I:C)-induced IFN-β production by targeting a molecule upstream of retinoic acid-induced gene I (RIG-I) and melanoma differentiation gene 5 (MDA5)...
May 17, 2017: Oncotarget
https://www.readbyqxmd.com/read/28580734/sars-unique-fold-in-the-rousettus-bat-coronavirus-hku9
#10
Robert G Hammond, Xuan Tan, Margaret A Johnson
The coronavirus nonstructural protein 3 (nsp3) is a multifunctional protein that comprises multiple structural domains. This protein assists viral polyprotein cleavage, host immune interference, and may play other roles in genome replication or transcription. Here, we report the solution NMR structure of a protein from the "SARS-unique region" of the bat coronavirus HKU9. The protein contains a frataxin fold or double-wing motif, which is an α + β fold that is associated with protein/protein interactions, DNA binding, and metal ion binding...
June 5, 2017: Protein Science: a Publication of the Protein Society
https://www.readbyqxmd.com/read/28573622/assessment-of-inhibition-of-ebola-virus-progeny-production-by-antiviral-compounds
#11
Darryl Falzarano
Assessment of small molecule compounds against filoviruses, such as Ebola virus, has identified numerous compounds that appear to have antiviral activity and should presumably be further investigated in animal efficacy trials. However, despite the many compounds that are purported to have good antiviral activity in in vitro studies, there are few instances where any efficacy has been reported in nonhuman primate models. Many of the high-throughput screening assays use reporter systems that only recapitulate a portion of the virus life cycle, while other assays only assess antiviral activity at relatively early time points...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/28560640/mers-cov-papain-like-protease-pl-pro-expression-purification-and-spectroscopic-thermodynamic-characterization
#12
Ajamaluddin Malik, Mohammad A Alsenaidy
Within a decade, MERS-CoV emerged with nearly four times higher case fatality rate than an earlier outbreak of SARS-CoV and spread out in 27 countries in short span of time. As an emerging virus, combating it requires an in-depth understanding of its molecular machinery. Therefore, conformational characterization studies of coronavirus proteins are necessary to advance our knowledge of the matter for the development of antiviral therapies. In this study, MERS-CoV papain-like protease (PL(pro)) was recombinantly expressed and purified...
June 2017: 3 Biotech
https://www.readbyqxmd.com/read/28555543/broad-spectrum-inhibition-of-common-respiratory-rna-viruses-by-a-pyrimidine-synthesis-inhibitor-with-involvement-of-the-host-antiviral-response
#13
Nam Nam Cheung, Kin Kui Lai, Jun Dai, Kin Hang Kok, Honglin Chen, Kwok-Hung Chan, Kwok-Yung Yuen, Richard Yi Tsun Kao
Our previous screening of 50 240 structurally diverse compounds led to the identification of 39 influenza A virus infection inhibitors (Kao R.Y., Yang D., Lau L.S., Tsui W.H., Hu L. et al. Nat Biotechnol 2010;28:600-605). Further screening of these compounds against common respiratory viruses led to the discovery of compound FA-613. This inhibitor exhibited low micromolar antiviral activity against various influenza A and B virus strains, including the highly pathogenic influenza A strains H5N1 and H7N9, enterovirus A71, respiratory syncytial virus, human rhinovirus A, SARS- and MERS-coronavirus...
May 30, 2017: Journal of General Virology
https://www.readbyqxmd.com/read/28541711/a-critical-review-on-ultrasensitive-spectroscopic-based-methods-for-high-throughput-monitoring-of-bacteria-during-infection-treatment
#14
Nicoleta Elena Dina, Alia Colniță, Tiberiu Szöke-Nagy, Alin Sebastian Porav
The world is in the midst of a pre-emptive public health emergency, one that is just as dramatic as the global aggressive viruses-related crises (Ebola, Zika, or SARS), but not as visible. The "superbugs" and their antimicrobial resistance (AMR) don't cause much public alarm or awareness, but provoke financial losses of $100 trillion annually [1] . This status quo review offers an overview of ultrasensitive methods for high-throughput monitoring of bacteria during infection treatment, the effects of antibiotics on bacteria at single-cell level and the challenges we will need to face in their detection due to the extraordinary capability of these "superbugs" to gain and constantly improve multiresistance to antibiotics...
May 25, 2017: Critical Reviews in Analytical Chemistry
https://www.readbyqxmd.com/read/28530544/the-second-generation-of-highly-potent-hepatitis-c-virus-hcv-ns3-4a-protease-inhibitors-evolutionary-design-based-on-tailor-made-amino-acids-synthesis-and-major-features-of-bio-activity
#15
Shuni Wang, Yibing Wang, Jiang Wang, Tatsunori Sato, Kunisuke Izawa, Vadim A Soloshonok, Hong Liu
Hepatitis C is a current pandemic liver disease caused by the hepatitis C virus (HCV) with high morbidity and mortality. Recently, the direct-acting antiviral agents (DAAs) targeting HCV NS3/4A, NS5A and NS5B have become the most effective therapies against HCV infection in the clinical treatment. Among them, the second-generation of NS3/4A inhibitors have emerged as the mainstay of the DAA therapies, which are derived from the peptide substrate of NS3/4A protease and modified with various tailor-made amino acids in order to achieve high sustained virologic response (SVR) against HCV...
May 22, 2017: Current Pharmaceutical Design
https://www.readbyqxmd.com/read/28527823/antiviral-escin-derivatives-from-the-seeds-of-aesculus-turbinata-blume-japanese-horse-chestnut
#16
Ji Won Kim, Thi-Kim-Quy Ha, Hyomoon Cho, Eunhee Kim, Sang Hee Shim, Jun-Li Yang, Won Keun Oh
Porcine epidemic diarrhea virus (PEDV) causes severe diarrhea and high fatality of piglets, influencing the swine industry. Japanese horse chestnut (seed of Aesculus turbinata) contains many saponin mixtures, called escins, and has been used for a long time as a traditional medicinal plant. Structure-activity relationship (SAR) studies on escins have revealed that acylations at C-21 and C-22 with angeloyl or tigloyl groups were important for their cytotoxic effects. However, the strong cytotoxicity of escins makes them hard to utilize for other diseases and to develop as nutraceuticals...
May 8, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28525279/double-winged-3-hydroxypyrimidine-2-4-diones-potent-and-selective-inhibition-against-hiv-1-rnase-h-with-significant-antiviral-activity
#17
Sanjeev Kumar V Vernekar, Jing Tang, Bulan Wu, Andrew D Huber, Mary C Casey, Nataliya Myshakina, Daniel J Wilson, Jayakanth Kankanala, Karen A Kirby, Michael A Parniak, Stefan G Sarafianos, Zhengqiang Wang
Human immunodeficiency virus (HIV) reverse transcriptase (RT)-associated ribonuclease H (RNase H) remains the only virally encoded enzymatic function yet to be exploited as an antiviral target. One of the possible challenges may be that targeting HIV RNase H is confronted with a steep substrate barrier. We have previously reported a 3-hydroxypyrimidine-2,4-dione (HPD) subtype that potently and selectively inhibited RNase H without inhibiting HIV in cell culture. We report herein a critical redesign of the HPD chemotype featuring an additional wing at the C5 position that led to drastically improved RNase H inhibition and significant antiviral activity...
May 31, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28494252/design-synthesis-and-primary-biological-evaluation-of-the-novel-2-pyridone-derivatives-as-potent-non-nucleoside-hbv-inhibitors
#18
Haiyong Jia, Yang Song, Ji Yu, Peng Zhan, Diwakar Rai, Xiaohong Liang, Chunhong Ma, Xinyong Liu
In continuation of our efforts toward the discovery of potent non-nucleoside hepatitis B virus (HBV) inhibitors with novel structures, we have employed bioisosterism and hybrid pharmacophore-based strategy to explore the chemically diverse space of bioactive compounds. Cytotoxicity, anti-HBV antigen secretion activities and anti-HBV DNA replication activity were assayed with cell counting kit-8 (CCK-8), enzyme linked immunosorbent assay (ELISA) and a real-time PCR, respectively. Some of the new compounds were able to inhibit the replication of HBV DNA activity in the low micromolar range...
April 24, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28475794/from-sars-to-avian-influenza-preparedness-in-hong-kong
#19
Andrew T Y Wong, Hong Chen, Shao-Haei Liu, Enoch K Hsu, Kristine S Luk, Christopher K C Lai, Regina F Y Chan, Owen T Y Tsang, K W Choi, Y W Kwan, Anna Y H Tong, Vincent C C Cheng, Dominic N C Tsang
The first human H5N1 case was diagnosed in Hong Kong in 1997. Since then, experience in effective preparedness strategies that target novel influenza viruses has expanded. Here, we report on avian influenza preparedness in public hospitals in Hong Kong to illustrate policies and practices associated with control of emerging infectious diseases. The Hong Kong government's risk-based preparedness plan for influenza pandemics includes 3 response levels for command, control, and coordination frameworks for territory-wide responses...
May 15, 2017: Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America
https://www.readbyqxmd.com/read/28466096/pathogenic-human-coronavirus-infections-causes-and-consequences-of-cytokine-storm-and-immunopathology
#20
REVIEW
Rudragouda Channappanavar, Stanley Perlman
Human coronaviruses (hCoVs) can be divided into low pathogenic and highly pathogenic coronaviruses. The low pathogenic CoVs infect the upper respiratory tract and cause mild, cold-like respiratory illness. In contrast, highly pathogenic hCoVs such as severe acute respiratory syndrome CoV (SARS-CoV) and Middle East respiratory syndrome CoV (MERS-CoV) predominantly infect lower airways and cause fatal pneumonia. Severe pneumonia caused by pathogenic hCoVs is often associated with rapid virus replication, massive inflammatory cell infiltration and elevated pro-inflammatory cytokine/chemokine responses resulting in acute lung injury (ALI), and acute respiratory distress syndrome (ARDS)...
May 2, 2017: Seminars in Immunopathology
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