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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
#1
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
#2
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
#3
Sanjeev Kumar V Vernekar, Jing Tang, Bulan Wu, Andrew D Huber, Mary C Casey, Nataliya S 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 19, 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
#4
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
#5
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
#6
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
https://www.readbyqxmd.com/read/28465101/drug-like-property-driven-optimization-of-4-substituted-1-5-diarylanilines-as-potent-hiv-1-non-nucleoside-reverse-transcriptase-inhibitors-against-rilpivirine-resistant-mutant-virus
#7
Lei Wei, Hui-Ling Wang, Li Huang, Chin-Ho Chen, Susan L Morris-Natschke, Kuo-Hsiung Lee, Lan Xie
On the basis of our prior structure-activity relationship (SAR) results, our current lead optimization of 1,5-diarylanilines (DAANs) focused on the 4-substituent (R(1)) on the central phenyl ring as a modifiable position related simultaneously to improved drug resistance profiles and drug-like properties. Newly synthesized p-cyanovinyl-DAANs (8a-8g) with different R(1) side chains plus prior active p-cyanoethyl-DAANs (4a-4c) were evaluated not only for anti-HIV potency against both wild-type HIV virus and rilpivirine-resistant (E138K, E138K+M184I) viral replication, but also for multiple drug-like properties, including aqueous solubility, lipophilicity, and metabolic stability in human liver microsomes and human plasma...
April 22, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28453839/virucidal-activity-of-world-health-organization-recommended-formulations-against-enveloped-viruses-including-zika-ebola-and-emerging-coronaviruses
#8
Anindya Siddharta, Stephanie Pfaender, Nathalie Jane Vielle, Ronald Dijkman, Martina Friesland, Britta Becker, Jaewon Yang, Michael Engelmann, Daniel Todt, Marc P Windisch, Florian H Brill, Joerg Steinmann, Jochen Steinmann, Stephan Becker, Marco P Alves, Thomas Pietschmann, Markus Eickmann, Volker Thiel, Eike Steinmann
The World Health Organization (WHO) published 2 alcohol-based formulations to be used in healthcare settings and for outbreak-associated infections, but inactivation efficacies of these products have not been determined against (re-)emerging viruses. In this study, we evaluated the virucidal activity of these WHO products in a comparative analysis. Zika virus (ZIKV), Ebola virus (EBOV), severe acute respiratory syndrome coronavirus (SARS-CoV), and Middle East respiratory syndrome coronavirus (MERS-CoV) as (re-)emerging viral pathogens and other enveloped viruses could be efficiently inactivated by both WHO formulations, implicating their use in healthcare systems and viral outbreak situations...
March 15, 2017: Journal of Infectious Diseases
https://www.readbyqxmd.com/read/28443114/tadir1-2-a-wheat-ortholog-of-lipid-transfer-protein-atdir1-contributes-to-negative-regulation-of-wheat-resistance-against-puccinia-striiformis-f-sp-tritici
#9
Soyed M Ahmed, Peng Liu, Qinghe Xue, Changan Ji, Tuo Qi, Jia Guo, Jun Guo, Zhensheng Kang
Very few LTPs have been shown to act through plasma membrane receptors or to be involved in the hypersensitive response (HR). DIR1, a new type of plant LTP interacts with lipids in vitro, moves to distant tissues during systemic acquired resistance (SAR) and therefore is thought to be involved in long-distance signaling during SAR. However, the exact functions of DIR1 orthologs in cereal species under biotic and abiotic stresses have not been thoroughly defined. In this study, a novel wheat ortholog of the DIR1 gene, TaDIR1-2, was isolated from Suwon11, a Chinese cultivar of wheat and functionally characterized...
2017: Frontiers in Plant Science
https://www.readbyqxmd.com/read/28438633/structural-insights-into-the-interaction-of-coronavirus-papain-like-proteases-and-interferon-stimulated-gene-product-15-from-different-species
#10
Courtney M Daczkowski, John V Dzimianski, Jozlyn R Clasman, Octavia Goodwin, Andrew D Mesecar, Scott D Pegan
Severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV) encode multifunctional papain-like proteases (PLPs) that have the ability to process the viral polyprotein to facilitate RNA replication and antagonize the host innate immune response. The latter function involves reversing the post-translational modification of cellular proteins conjugated with either ubiquitin (Ub) or Ub-like interferon-stimulated gene product 15 (ISG15). Ub is known to be highly conserved among eukaryotes, but surprisingly, ISG15 is highly divergent among animals...
April 21, 2017: Journal of Molecular Biology
https://www.readbyqxmd.com/read/28430149/synthesis-and-antiviral-activity-of-novel-1-4-pentadien-3-one-derivatives-containing-a-1-3-4-thiadiazole-moiety
#11
Lu Yu, Xiuhai Gan, Dagui Zhou, Fangcheng He, Song Zeng, Deyu Hu
1,4-Pentadien-3-one derivatives derived from curcumin possess excellent inhibitory activity against plant viruses. On the basis of this finding, a series of novel 1,4-pentadien-3-one derivatives containing a 1,3,4-thiadiazole moiety were designed and synthesized, and their structures confirmed by IR, ¹H-NMR, and (13)C-NMR spectroscopy and elemental analysis. The antiviral activities of the title compounds were evaluated against tobacco mosaic virus (TMV) and cucumber mosaic virus (CMV) in vivo. The assay results showed that most of compounds had remarkable antiviral activities against TMV and CMV, among which compounds 4b, 4h, 4i, 4k, 4o, and 4q exhibited good curative, protection, and inactivation activity against TMV...
April 21, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/28418771/persistence-in-temporary-lung-niches-a-survival-strategy-of-lung-resident-memory-cd8-t-cells
#12
Shiki Takamura
Respiratory virus infections, such as those mediated by influenza virus, parainfluenza virus, respiratory syncytial virus (RSV), severe acute respiratory syndrome coronavirus (SARS-CoV), rhinovirus, and adenovirus, are responsible for substantial morbidity and mortality, especially in children and older adults. Furthermore, the potential emergence of highly pathogenic strains of influenza virus poses a significant public health threat. Thus, the development of vaccines capable of eliciting long-lasting protective immunity to those pathogens is a major public health priority...
April 18, 2017: Viral Immunology
https://www.readbyqxmd.com/read/28416550/identification-and-optimization-of-thienopyridine-carboxamides-as-inhibitors-of-hiv-regulatory-complexes
#13
Robert L Nakamura, Mark A Burlingame, Shumin Yang, David C Crosby, Dale J Talbot, Kitty Chui, Alan D Frankel, Adam R Renslo
Viral regulatory complexes perform critical functions during virus replication and are important targets for therapeutic intervention. In HIV, the Tat and Rev proteins form complexes with multiple viral and cellular factors to direct transcription and export of the viral RNA. These complexes are composed of many proteins and are dynamic, making them difficult to fully recapitulate in vitro Therefore we developed a cell-based reporter assay to monitor the assembly of viral complexes for inhibitor screening. We screened a small molecule library and identified multiple hits that inhibit the activity of the viral complexes...
April 17, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28405626/basic-scholarship-in-biosafety-is-critically-needed-to-reduce-risk-of-laboratory-accidents
#14
Ryan Ritterson, Rocco Casagrande
Our firm conducted a risk/benefit assessment of "gain-of-function" research, as part of the deliberative process following a U.S. moratorium on the research (U.S. Department of Health and Human Services, U.S. Government Gain-of-Function Deliberative Process and Research Funding Pause on Selected Gain-of-Function Research Involving Influenza, MERS, and SARS Viruses, 2014). Due to significant missing but theoretically acquirable data, our biosafety assessment faced limitations, and we were forced to provide a relative, instead of absolute, measure of risk (Gryphon Scientific, LLC, Risk and Benefit Analysis of Gain of Function Research, 2016)...
March 2017: MSphere
https://www.readbyqxmd.com/read/28404843/overactive-egfr-signaling-leads-to-increased-fibrosis-after-sars-cov-infection
#15
Thiagarajan Venkataraman, Christopher Coleman, Matthew Frieman
Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) is a highly pathogenic respiratory virus that causes morbidity and mortality in humans. After infection with SARS-CoV, the acute lung injury caused by the virus must be repaired to regain lung function. A dysregulation in this wound healing process leads to fibrosis. Many survivors of SARS-CoV infection develop pulmonary fibrosis (PF) with higher prevalence in older patients. Using mouse models of SARS-CoV pathogenesis, we have identified that the wound repair pathway, controlled by the Epidermal Growth Factor Receptor (EGFR) is critical to recovery from SARS-CoV induced tissue damage...
April 12, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28393837/cryo-em-structures-of-mers-cov-and-sars-cov-spike-glycoproteins-reveal-the-dynamic-receptor-binding-domains
#16
Yuan Yuan, Duanfang Cao, Yanfang Zhang, Jun Ma, Jianxun Qi, Qihui Wang, Guangwen Lu, Ying Wu, Jinghua Yan, Yi Shi, Xinzheng Zhang, George F Gao
The envelope spike (S) proteins of MERS-CoV and SARS-CoV determine the virus host tropism and entry into host cells, and constitute a promising target for the development of prophylactics and therapeutics. Here, we present high-resolution structures of the trimeric MERS-CoV and SARS-CoV S proteins in its pre-fusion conformation by single particle cryo-electron microscopy. The overall structures resemble that from other coronaviruses including HKU1, MHV and NL63 reported recently, with the exception of the receptor binding domain (RBD)...
April 10, 2017: Nature Communications
https://www.readbyqxmd.com/read/28390872/the-role-of-epidermal-growth-factor-receptor-egfr-signaling-in-sars-coronavirus-induced-pulmonary-fibrosis
#17
REVIEW
Thiagarajan Venkataraman, Matthew B Frieman
Many survivors of the 2003 outbreak of severe acute respiratory syndrome (SARS) developed residual pulmonary fibrosis with increased severity seen in older patients. Autopsies of patients that died from SARS also showed fibrosis to varying extents. Pulmonary fibrosis can be occasionally seen as a consequence to several respiratory viral infections but is much more common after a SARS coronavirus (SARS-CoV) infection. Given the threat of future outbreaks of severe coronavirus disease, including Middle East respiratory syndrome (MERS), it is important to understand the mechanisms responsible for pulmonary fibrosis, so as to support the development of therapeutic countermeasures and mitigate sequelae of infection...
April 5, 2017: Antiviral Research
https://www.readbyqxmd.com/read/28384506/extensive-diversity-of-coronaviruses-in-bats-from-china
#18
Xian-Dan Lin, Wen Wang, Zong-Yu Hao, Zhao-Xiao Wang, Wen-Ping Guo, Xiao-Qing Guan, Miao-Ruo Wang, Hong-Wei Wang, Run-Hong Zhou, Ming-Hui Li, Guang-Peng Tang, Jun Wu, Edward C Holmes, Yong-Zhen Zhang
To help reveal the diversity and evolution of bat coronaviruses we collected 1067 bats from 21 species in China. A total of 73 coronaviruses (32 alphacoronaviruses and 41 betacoronaviruses) were identified in these bats, with an overall prevalence of 6.84%. All newly-identified betacoronaviruses were SARS-related Rhinolophus bat coronaviruses (SARSr-Rh-BatCoV). Importantly, with the exception of the S gene, the genome sequences of the SARSr-Rh-BatCoVs sampled in Guizhou province were closely related to SARS-related human coronavirus...
April 3, 2017: Virology
https://www.readbyqxmd.com/read/28381569/group-a-rotaviruses-in-chinese-bats-genetic-composition-serology-and-evidence-for-bat-to-human-transmission-and-reassortment
#19
Biao He, Xiaohong Huang, Fuqiang Zhang, Weilong Tan, Jelle Matthijnssens, Shaomin Qin, Lin Xu, Zihan Zhao, Ling'en Yang, Quanxi Wang, Tingsong Hu, Xiaolei Bao, Jianmin Wu, Changchun Tu
Bats are natural reservoirs for many pathogenic viruses and increasing evidence supports that bats can also harbor group A rotaviruses (RVA), important causative agents of diarrhea in children and young animals. Currently, 8 RVA strains have been identified from African and Chinese bats, possessing completely novel genotype constellations or genotypes possibly originating from other mammals. However, all these data were mainly based on detection of RVA RNA, only present during acute infections, which does not permit assessment of the true exposure of a bat population to RVA...
April 5, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28373583/sex-based-differences-in-susceptibility-to-severe-acute-respiratory-syndrome-coronavirus-infection
#20
Rudragouda Channappanavar, Craig Fett, Matthias Mack, Patrick P Ten Eyck, David K Meyerholz, Stanley Perlman
Pathogenic human coronaviruses (CoVs), such as the severe acute respiratory syndrome (SARS)-CoV and the Middle East respiratory syndrome-CoV, cause acute respiratory illness. Epidemiological data from the 2002-2003 SARS epidemic and recent Middle East respiratory syndrome outbreak indicate that there may be sex-dependent differences in disease outcomes. To investigate these differences, we infected male and female mice of different age groups with SARS-CoV and analyzed their susceptibility to the infection...
May 15, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
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