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Satoru Noji, Noriyoshi Seki, Takaki Maeba, Takayuki Sakai, Eiichi Watanabe, Katsuya Maeda, Kyoko Fukushima, Toru Noguchi, Kazuya Ogawa, Yukiyo Toyonaga, Tamotsu Negoro, Hisashi Kawasaki, Makoto Shiozaki
In typical kinase inhibitor programs, a hinge binder showing best potency with preferential specificity is initially selected, followed by fine-tuning of the accompanying substituents on its core module. A shortcoming of this approach is that the exclusive focus on a single chemotype can endanger all the analogues in the series if a critical shortcoming is revealed. Thus, an early evaluation of structure-activity relationships (SARs) can mitigate unforeseen outcomes within a series of multiple compounds, although there have been very few examples to follow such a policy...
October 13, 2016: ACS Medicinal Chemistry Letters
Kazuya Shirato, Kazuhiko Kanou, Miyuki Kawase, Shutoku Matsuyama
: Human coronavirus 229E (HCoV-229E), a causative agent of the common cold, enters host cells via two distinct pathways: one is mediated by cell surface proteases, particularly transmembrane protease serine 2 (TMPRSS2), and the other by endosomal cathepsin L. Thus, specific inhibitors of these proteases block virus infection. However, it is unclear which of these pathways is actually utilized by HCoV-229E in the human respiratory tract. Here, we examined the mechanism of cell entry used by a pseudotyped virus bearing the HCoV-229E spike (S) protein in the presence/absence of protease inhibitors...
October 12, 2016: Journal of Virology
Hainv Gao, Hangping Yao, Shigui Yang, Lanjuan Li
The Middle East respiratory syndrome coronavirus (MERS-CoV) is a novel zoonotic pathogen. In 2012, the infectious outbreak caused by MERS-CoV in Saudi Arabia has spread to more than 1600 patients in 26 countries, resulting in over 600 deaths.Without a travel history, few clinical and radiological features can reliably differentiate MERS from SARS. But in real world, comparing with SARS, MERS presents more vaguely defined epidemiology, more severe symptoms, and higher case fatality rate. In this review, we summarize the recent findings in the field of MERS-CoV, especially its molecular virology, interspecies mechanisms, clinical features, antiviral therapies, and the further investigation into this disease...
October 1, 2016: Frontiers of Medicine
Ana Carolina Diniz Matos, Mario Felipe Alvarez Balaro, Maria Isabel Maldonado Coelho Guedes, Erica Azevedo Costa, Ju Lio Ce Sar Ca Mara Rosa, Aristo Teles Gomes Costa, Felipe Zandonadi Branda O, Ze Lia Ine S Portela Lobato
In January 2013, an outbreak of Bluetongue (BT) a ecting a Lacaune sheep ock occurred in Vassouras, Rio de Janeiro state, Brazil. From March to August 2013, blood samples collection and clinical examination were performed monthly, in order to monitor the epidemiological pro le of Bluetongue virus (BTV) circulation and clinical disease in the ock. Agar gel immunodi usion (AGID) and reverse transcription polymerase chain reaction (RT-PCR) targeting BTV segment 10 were used as diagnostic assays. Additionally, insect trapping was conducted in the farm from May to July 2013...
September 30, 2016: Veterinaria Italiana
Zhibing Weng, Xiaoxia Shao, Dominik Graf, Chunguang Wang, Christian D Klein, Jing Wang, Guo-Chun Zhou
A series of fused ring derivatives of pyrrolidine and imidazolidinone were designed, synthesized, characterized and assayed against the DENV-2 NS2B-NS3 protease and wild-type DENV-2 virus. The linear dipeptide compound 1 and the non-peptidic fused ring compound 2 show comparable activities against DENV-2 NS2B-NS3 protease and wild-type DENV-2 virus in a viral replication assay. The preliminary SAR reveals that a substituent and its stereochemistry at C-3 position, substitution (X) at N-2 arene and a linker (Y) between C-3 position and its attached arene are important for the fused-ring scaffold of pyrrolidino [1,2-c]imidazolidinone to block the active site of NS2B-NS3 protease...
September 21, 2016: European Journal of Medicinal Chemistry
Xiang Xu, John R Greenland, Jeffrey E Gotts, Michael A Matthay, George H Caughey
Host-derived proteases can augment or help to clear infections. This dichotomy is exemplified by cathepsin L (CTSL), which helps Hendra virus and SARS coronavirus to invade cells, but is essential for survival in mice with mycoplasma pneumonia. The present study tested the hypothesis that CTSL protects mice from serious consequences of infection by the orthomyxovirus influenza A, which is thought to be activated by host-supplied proteases other than CTSL. Ctsl-/- mice infected with influenza A/Puerto Rico/8/34(H1N1) had larger lung viral loads and higher mortality than infected Ctsl+/+ mice...
2016: PloS One
E J Snijder, E Decroly, J Ziebuhr
Coronaviruses are animal and human pathogens that can cause lethal zoonotic infections like SARS and MERS. They have polycistronic plus-stranded RNA genomes and belong to the order Nidovirales, a diverse group of viruses for which common ancestry was inferred from the common principles underlying their genome organization and expression, and from the conservation of an array of core replicase domains, including key RNA-synthesizing enzymes. Coronavirus genomes (~26-32 kilobases) are the largest RNA genomes known to date and their expansion was likely enabled by acquiring enzyme functions that counter the commonly high error frequency of viral RNA polymerases...
2016: Advances in Virus Research
R J G Hulswit, C A M de Haan, B-J Bosch
Coronaviruses (CoVs) have a remarkable potential to change tropism. This is particularly illustrated over the last 15 years by the emergence of two zoonotic CoVs, the severe acute respiratory syndrome (SARS)- and Middle East respiratory syndrome (MERS)-CoV. Due to their inherent genetic variability, it is inevitable that new cross-species transmission events of these enveloped, positive-stranded RNA viruses will occur. Research into these medical and veterinary important pathogens-sparked by the SARS and MERS outbreaks-revealed important principles of inter- and intraspecies tropism changes...
2016: Advances in Virus Research
L Enjuanes, S Zuñiga, C Castaño-Rodriguez, J Gutierrez-Alvarez, J Canton, I Sola
Virus vaccines have to be immunogenic, sufficiently stable, safe, and suitable to induce long-lasting immunity. To meet these requirements, vaccine studies need to provide a comprehensive understanding of (i) the protective roles of antiviral B and T-cell-mediated immune responses, (ii) the complexity and plasticity of major viral antigens, and (iii) virus molecular biology and pathogenesis. There are many types of vaccines including subunit vaccines, whole-inactivated virus, vectored, and live-attenuated virus vaccines, each of which featuring specific advantages and limitations...
2016: Advances in Virus Research
Paulo G Hofstatter, Alexander K Tice, Seungho Kang, Matthew W Brown, Daniel J G Lahr
Recombinase enzymes promote DNA repair by homologous recombination. The genes that encode them are ancestral to life, occurring in all known dominions: viruses, Eubacteria, Archaea and Eukaryota. Bacterial recombinases are also present in viruses and eukaryotic groups (supergroups), presumably via ancestral events of lateral gene transfer. The eukaryotic recA genes have two distinct origins (mitochondrial and plastidial), whose acquisition by eukaryotes was possible via primary (bacteria-eukaryote) and/or secondary (eukaryote-eukaryote) endosymbiotic gene transfers (EGTs)...
October 12, 2016: Proceedings. Biological Sciences
Canping Huang, Jianxun Qi, Guang-Wen Lu, Qihui Wang, Yuan Yuan, Ying Wu, Yanfang Zhang, Jinghua Yan, George F Gao
The suggested bat-origin for Middle East respiratory syndrome coronavirus (MERS-CoV) has revitalized the studies on other bat-derived coronaviruses for the interspecies transmission potential. Bat coronavirus (BatCoV) HKU9 is an important betacoronavirus (betaCoV) that is phylogenetically affiliated to the same genus as MERS-CoV. The bat-surveillance data indicated that BatCoV HKU9 has been widely spreading and circulating in bats. This highlights the necessity of characterizing the virus for its potential of crossing species barriers...
October 3, 2016: Biochemistry
Canping Huang, William J Liu, Wen Xu, Tao Jin, Yingze Zhao, Jingdong Song, Yi Shi, Wei Ji, Hao Jia, Yongming Zhou, Honghua Wen, Honglan Zhao, Huaxing Liu, Hong Li, Qihui Wang, Ying Wu, Liang Wang, Di Liu, Guang Liu, Hongjie Yu, Edward C Holmes, Lin Lu, George F Gao
The emergence of severe acute respiratory syndrome coronavirus (SARS-CoV) in 2002 and Middle East respiratory syndrome coronavirus (MERS-CoV) in 2012 has generated enormous interest in the biodiversity, genomics and cross-species transmission potential of coronaviruses, especially those from bats, the second most speciose order of mammals. Herein, we identified a novel coronavirus, provisionally designated Rousettus bat coronavirus GCCDC1 (Ro-BatCoV GCCDC1), in the rectal swab samples of Rousettus leschenaulti bats by using pan-coronavirus RT-PCR and next-generation sequencing...
September 2016: PLoS Pathogens
Jason E McDermott, Hugh D Mitchell, Lisa E Gralinski, Amie J Eisfeld, Laurence Josset, Armand Bankhead, Gabriele Neumann, Susan C Tilton, Alexandra Schäfer, Chengjun Li, Shufang Fan, Shannon McWeeney, Ralph S Baric, Michael G Katze, Katrina M Waters
BACKGROUND: The complex interplay between viral replication and host immune response during infection remains poorly understood. While many viruses are known to employ anti-immune strategies to facilitate their replication, highly pathogenic virus infections can also cause an excessive immune response that exacerbates, rather than reduces pathogenicity. To investigate this dichotomy in severe acute respiratory syndrome coronavirus (SARS-CoV), we developed a transcriptional network model of SARS-CoV infection in mice and used the model to prioritize candidate regulatory targets for further investigation...
2016: BMC Systems Biology
Shuang-Xi Gu, Ping Xue, Xiu-Lian Ju, Yuan-Yuan Zhu
Reverse transcriptase (RT) and integrase (IN) are two indispensable enzymes in human immunodeficiency virus type 1 (HIV-1) replication. RT is responsible for the transformation of the single-stranded RNA viral genome into double-stranded DNA, and IN catalyzes the integration of viral DNA into the host DNA. Although highly active antiretroviral therapy (HAART) combining nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs/NtRTIs) with nonnucleoside reverse transcriptase inhibitors (NNRTIs) or protease inhibitors (PIs) could suppress successfully HIV viral load and reduce evidently the mortality of HIV infected people, it involves the difficulty of perfect adherence, and other drawbacks such as viral rebound, toxicities and multi-drug resistances...
November 1, 2016: Bioorganic & Medicinal Chemistry
C Chidiac, T Ferry
Emergence of many emerging or re-emerging infectious diseases have occurred over the past decade, some of which are major public threat. SARS, MERS-CoV, highly pathogenic avian influenza A(H5N1), Ebola virus disease have raised concerns because of their virulence, their mortality, and/or their modality of transmission, or their impact on maternofoetal transmission (Zika virus). The witness of these emergences have conducted health authorities to have policies and plans and to imagine new organizations for health systems in order to identify any case of highly communicable virulent disease for immediate isolation, and adequate management...
September 16, 2016: Transfusion Clinique et Biologique: Journal de la Société Française de Transfusion Sanguine
Simona Musella, Veronica di Sarno, Tania Ciaglia, Marina Sala, Antonia Spensiero, Maria Carmina Scala, Carmine Ostacolo, Graciela Andrei, Jan Balzarini, Robert Snoeck, Ettore Novellino, Pietro Campiglia, Alessia Bertamino, Isabel M Gomez-Monterrey
We report the synthesis and antiviral activity of a new family of non-nucleoside antivirals, derived from the indole nucleus. Modifications of this template through Mannich and Friedel-Crafts reactions, coupled with nucleophilic displacement and reductive aminations led to 23 final derivatives, which were pharmacologically tested. Tryptamine derivative 17a was found to have a selective inhibitory activity against human varicella zoster virus (VZV) replication in vitro, being inactive against a variety of other DNA and RNA viruses...
September 7, 2016: European Journal of Medicinal Chemistry
Na Ye, Haiying Chen, Eric A Wold, Pei-Yong Shi, Jia Zhou
Antiviral therapeutics with profiles of high potency, low resistance, panserotype, and low toxicity remain challenging, and obtaining such agents continues to be an active area of therapeutic development. Due to their unique three-dimensional structural features, spirooxindoles have been identified as privileged chemotypes for antiviral drug development. Among them, spiro-pyrazolopyridone oxindoles have been recently reported as potent inhibitors of dengue virus NS4B, leading to the discovery of an orally bioavailable preclinical candidate (R)-44 with excellent in vivo efficacy in a dengue viremia mouse model...
June 10, 2016: ACS Infectious Diseases
Jie Zhou, Jie Wu, Xianqiao Zeng, Guofeng Huang, Lirong Zou, Yingchao Song, Divya Gopinath, Xin Zhang, Min Kang, Jinyan Lin, Benjamin J Cowling, William G Lindsley, Changwen Ke, Joseph Sriyal Malik Peiris, Hui-Ling Yen
Zoonotic infections by avian influenza viruses occur at the human-poultry interface, but the modes of transmission have not been fully investigated. We assessed the potential for airborne and fomite transmission at live poultry markets in Guangzhou city and in Hong Kong Special Administrative Region (SAR), China, during 2014 and 2015. Viral genome and infectious avian influenza A viruses of H5N6, H7N9, and H9N2 subtypes were detected predominantly from particles larger or equal to 1 μm in diameter in the air sampled with cyclone-based bioaerosol samplers at the live poultry markets in Guangzhou...
September 1, 2016: Euro Surveillance: Bulletin Européen sur les Maladies Transmissibles, European Communicable Disease Bulletin
Linwei Chen, Yongxian Liu, Hongjian Song, Yuxiu Liu, Lizhong Wang, Qingmin Wang
To systematically investigate the influence of the variation of the original skeletons and spatial configuration of 2,3-fused indole natural products on antiviral activities, two types of structurally novel and potent pseudo-indole natural product derivatives, 1,2-fused indole and spiroindoline, with different substituents were direct synthesized from 2-halo anilines, and their antiviral activities against tobacco mosaic virus (TMV) were evaluated. The results showed that these compounds exhibited good anti-TMV activity, especially 3f, 3g, 3i, 5e, 5h, and 5l, which were more potent than the commercial anti-virus agent ribavirin...
September 3, 2016: Molecular Diversity
Yin Mo, Dale Fisher
The Middle East Respiratory Syndrome coronavirus (MERS-CoV) has been a focus of international attention since its identification in 2012. Epidemiologically it is characterized by sporadic community cases, which are amplified by hospital-based outbreaks. Healthcare facilities in 27 countries from most continents have experienced imported cases, with the most significant outbreak involving 186 cases in Korea. The mortality internationally is 36% and guidance for clinical management has yet to be developed. Most facilities and healthcare providers outside of the Middle East receiving patients have no or little experience in the clinical management of MERS...
September 1, 2016: Journal of Antimicrobial Chemotherapy
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