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Julia Sommer, Susanne Fister, Tobias Gundolf, Birgit Bromberger, Patrick-Julian Mester, Anna Kristina Witte, Roland Kalb, Peter Rossmanith
For three decades now, ionic liquids (ILs), organic salts comprising only ions, have emerged as a new class of pharmaceuticals. Although recognition of the antimicrobial effects of ILs is growing rapidly, there is almost nothing known about their possible virucidal activities. This probably reflects the paucity of understanding virus inactivation. In this study, we performed a systematic analysis to determine the effect of specific structural motifs of ILs on three different biological test systems (viruses, bacteria and enzymes)...
March 9, 2018: International Journal of Molecular Sciences
Tatiana Schäffer Gregianini, Claudete Farina Seadi, Ivone Menegolla, Letícia Garay Martins, Nilo Ikuta, Jonas Michel Wolf, Vagner Ricardo Lunge
INTRODUCTION: Infections caused by respiratory viruses are important problems worldwide, especially in children. Human metapneumovirus (hMPV) is a respiratory pathogen and causes severe infections with nonspecific symptoms. This study reports the hMPV occurrence and dissemination in southern Brazil and compares the frequency of occurrence of this virus and the human respiratory syncytial virus (hRSV) in the epidemiological weeks in a three-year period (2009-2011). METHODS: In total, 545 nasopharyngeal (NP) specimens from individuals with Severe Acute Respiratory Syndrome (SARS) who were negative for other seven respiratory viruses were analyzed for the presence of hMPV...
January 2018: Revista da Sociedade Brasileira de Medicina Tropical
Patrick C Y Woo, Susanna K P Lau, Yixin Chen, Emily Y M Wong, Kwok-Hung Chan, Honglin Chen, Libiao Zhang, Ningshao Xia, Kwok-Yung Yuen
Recently, we developed a monoclonal antibody-based rapid nucleocapsid protein detection assay for diagnosis of MERS coronavirus (MERS-CoV) in humans and dromedary camels. In this study, we examined the usefulness of this assay to detect other lineage C betacoronaviruses closely related to MERS-CoV in bats. The rapid MERS-CoV nucleocapsid protein detection assay was tested positive in 24 (88.9%) of 27 Tylonycteris bat CoV HKU4 (Ty-BatCoV-HKU4) RNA-positive alimentary samples of Tylonycteris pachypus and 4 (19...
March 7, 2018: Emerging Microbes & Infections
Maria L Agostini, Erica L Andres, Amy C Sims, Rachel L Graham, Timothy P Sheahan, Xiaotao Lu, Everett Clinton Smith, James Brett Case, Joy Y Feng, Robert Jordan, Adrian S Ray, Tomas Cihlar, Dustin Siegel, Richard L Mackman, Michael O Clarke, Ralph S Baric, Mark R Denison
Emerging coronaviruses (CoVs) cause severe disease in humans, but no approved therapeutics are available. The CoV nsp14 exoribonuclease (ExoN) has complicated development of antiviral nucleosides due to its proofreading activity. We recently reported that the nucleoside analogue GS-5734 (remdesivir) potently inhibits human and zoonotic CoVs in vitro and in a severe acute respiratory syndrome coronavirus (SARS-CoV) mouse model. However, studies with GS-5734 have not reported resistance associated with GS-5734, nor do we understand the action of GS-5734 in wild-type (WT) proofreading CoVs...
March 6, 2018: MBio
Xin Zhang, Qiang Liu, Na Zhang, Qian-Qian Li, Zhan-Dong Liu, Ying-Hong Li, Li-Mei Gao, You-Chun Wang, Hong-Bin Deng, Dan-Qing Song
Preventing filoviruses in the entry stage is an attractive antiviral strategy. Taking aloperine, a Chinese natural herb with an endocyclic skeleton, as the lead, 23 new aloperine derivatives were synthesized and evaluated for their anti-filovirus activities including ebola virus (EBOV) and marburg virus (MARV) using pseudotyped virus model. Structure-activity relationship (SAR) analysis indicated that the introduction of a 12N-dichlorobenzyl group was beneficial for the potency. Compound 2e exhibited the most potent anti-EBOV and anti-MARV effects both in vitro and in vivo...
February 26, 2018: European Journal of Medicinal Chemistry
Arinjay Banerjee, Vikram Misra, Tony Schountz, Michelle L Baker
Bats are natural reservoirs for a variety of emerging viruses that cause significant disease in humans and domestic animals yet rarely cause clinical disease in bats. The co-evolutionary history of bats with viruses has been hypothesized to have shaped the bat-virus relationship, allowing both to exist in equilibrium. Progress in understanding bat-virus interactions and the isolation of bat-borne viruses has been accelerated in recent years by the development of susceptible bat cell lines. Viral sequences similar to severe acute respiratory syndrome corona virus (SARS-CoV) have been detected in bats, and filoviruses such as Marburg virus have been isolated from bats, providing definitive evidence for the role of bats as the natural host reservoir...
March 15, 2018: Virus Research
Harshil R Shah, Jignasa Ketan Savjani
The healthcare system faces various challenges in human immunodeficiency virus (HIV) therapy due to resistance to Anti-Retroviral Therapy (ART) as a consequence of the evolutionary process. Despite the success of antiretroviral drugs like Zidovudine, Zalcitabine, Raltegravir WHO ranks HIV as one of the deadliest diseases with a mortality of one million lives in 2016. Thus, there emerges an urgency of developing a novel anti-retroviral agent that combat resistant HIV strains. The clinical development of ART from a single drug regimen to current triple drug combination is very slow...
March 10, 2018: European Journal of Medicinal Chemistry
Valeria Famiglini, Romano Silvestri
Indolylarylsulfones are a potent class of human immunodeficiency virus type 1 non-nucleoside reverse transcriptase inhibitors. In this review, the structure activity relationship (SAR) studies to improve the profile of sulfone L-737,126 discovered by Merck AG have been analysed with focus on introduction of the 3',5'-dimethyl groups at the 3-phenylsulfonyl moiety, the 2-hydroxyethyl tail at the indole-2-carboxamide nitrogen, coupling of the carboxamide nitrogen with one or two glycinamide and alaninamide units, a fluorine atom at position 4 of the indole ring and correlation between configuration of the asymmetric centre and linker length...
January 2018: Antiviral Chemistry & Chemotherapy
Phanramphoei N Frantz, Samaporn Teeravechyan, Frédéric Tangy
Infectious disease epidemics match wars and natural disasters in their capacity to threaten lives and damage economies. Like SARS previously and Zika recently, the Ebola crisis in 2015 showed how vulnerable the world is to these epidemics, with over 11,000 people dying in the outbreak. In addition to causing immense human suffering, these epidemics particularly affect low- and middle-income countries. Many of these deadly infectious diseases that have epidemic potential can become global health emergencies in the absence of effective vaccines...
January 31, 2018: Microbes and Infection
Vineet D Menachery, Alexandra Schäfer, Kristin E Burnum-Johnson, Hugh D Mitchell, Amie J Eisfeld, Kevin B Walters, Carrie D Nicora, Samuel O Purvine, Cameron P Casey, Matthew E Monroe, Karl K Weitz, Kelly G Stratton, Bobbie-Jo M Webb-Robertson, Lisa E Gralinski, Thomas O Metz, Richard D Smith, Katrina M Waters, Amy C Sims, Yoshihiro Kawaoka, Ralph S Baric
Convergent evolution dictates that diverse groups of viruses will target both similar and distinct host pathways to manipulate the immune response and improve infection. In this study, we sought to leverage this uneven viral antagonism to identify critical host factors that govern disease outcome. Utilizing a systems-based approach, we examined differential regulation of IFN-γ-dependent genes following infection with robust respiratory viruses including influenza viruses [A/influenza/Vietnam/1203/2004 (H5N1-VN1203) and A/influenza/California/04/2009 (H1N1-CA04)] and coronaviruses [severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome CoV (MERS-CoV)]...
January 16, 2018: Proceedings of the National Academy of Sciences of the United States of America
Dong Lu, Jianan Liu, Yunzhe Zhang, Feifei Liu, Limin Zeng, Runze Peng, Li Yang, Huazhou Ying, Wei Tang, Wuhong Chen, Jianping Zuo, Xiankun Tong, Tao Liu, Youhong Hu
Using a dengue replicon cell line-based screening, we identified 3-(dimethylamino)propyl(3-((4-(4-fluorophenyl)-1-oxophthalazin-2(1H)-yl)methyl)phenyl)carbamate (10a) as a potent DENV-2 inhibitor, with an IC50 value of 0.64 μM. A series of novel phthalazinone derivatives based on hit 10a were synthesized and evaluated for their in vitro anti-DENV activity and cytotoxicity. The subsequent SAR study and optimization led to the discovery of the most promising compound 14l, which displayed potent anti-DENV-2 activity, with low IC50 value against DENV-2 RNA replication of 0...
January 5, 2018: European Journal of Medicinal Chemistry
Mathieu Bourgarel, Davies M Pfukenyi, Vanina Boué, Loïc Talignani, Ngoni Chiweshe, Fodé Diop, Alexandre Caron, Gift Matope, Dorothée Missé, Florian Liégeois
Bats carry a great diversity of zoonotic viruses with a high-impact on human health and livestock. Since the emergence of new coronaviruses and paramyxoviruses in humans (e.g. Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) and Nipah virus), numerous studies clearly established that bats can maintain some of these viruses. Improving our understanding on the role of bats in the epidemiology of the pathogens they harbour is necessary to prevent cross-species spill over along the wild/domestic/human gradient...
January 10, 2018: Infection, Genetics and Evolution
Xiyuan Wu, Zixuan Liu, Xiaohui Ding, Danwei Yu, Huamian Wei, Bo Qin, Yuanmei Zhu, Huihui Chong, Sheng Cui, Yuxian He
SC29EK is an electronically constrained α-helical peptide HIV-1 fusion inhibitor highly effective against both wild-type and enfuvirtide (T20)-resistant viruses. In this study, we focused on investigating the mechanism of HIV-1 resistance to SC29EK by two approaches. First, SC29EK-escaping HIV-1 variants were selected and characterized. Three mutant viruses, which possessed two (E43K/E49A) or three (Q39R/N43K/N126K, N43K/E49A/N126K) amino acid substitutions in the N- and C-terminal repeat regions of gp41 were identified as conferring high resistance to SC29EK and cross-resistance to the first-generation (T20, C34) and newly-designed (sifuvirtide, MT-SC29EK, 2P23) fusion inhibitors...
January 10, 2018: Journal of Virology
Ying Wang, Shao-Ru Chen, Xiaoming Yang, Kuo-Hsiung Lee, Yung-Chi Cheng
The tylophorine analog rac-cryptopleurine exhibited potent anti-hepatitis C virus (HCV) activity through allosteric regulation of ATPase activity of heat shock cognate protein 70 (Hsc70). We evaluated the impact of modifications on the E-ring of rac-cryptopleurine to the inhibitory activity against HCV replication and regulation of ATPase activity of Hsc70. Cryptopleurine analog YXM-110 with a 13α-hydroxyl group maintained activity against HCV and promoted ATP/ADP turnover of Hsc70; however, compounds with hydroxyl groups at other positions or with other orientations (YXM-109, YXM-139, and YXM-140) did not exhibit similar activities...
December 20, 2017: Bioorganic & Medicinal Chemistry
Joseph O Obameso, Hong Li, Hao Jia, Min Han, Shiyan Zhu, Canping Huang, Yuhui Zhao, Min Zhao, Yu Bai, Fei Yuan, Honglan Zhao, Xia Peng, Wen Xu, Wenjie Tan, Yingze Zhao, Kwok-Yung Yuen, William J Liu, Lin Lu, George F Gao
Bats are connected with the increasing numbers of emerging and re-emerging viruses that may break the species barrier and spread into the human population. Coronaviruses are one of the most common viruses discovered in bats, which were considered as the natural source of recent human-susceptible coronaviruses, i.e. SARS-COV and MERS-CoV. Our previous study reported the discovery of a bat-derived putative cross-family recombinant coronavirus with a reovirus gene p10, named as Ro-BatCoV GCCDC1. In this report, through a two-year follow-up of a special bat population in one specific cave of south China, we illustrate that Ro-BatCoV GCCDC1 persistently circulates among bats...
December 1, 2017: Science China. Life Sciences
Paul Turner, Kuong Suy, Le Van Tan, Pora Sar, Thyl Miliya, Nguyen Thi Thu Hong, Vu Thi Ty Hang, Nguyen Thi Han Ny, Sona Soeng, Nicholas P J Day, H Rogier van Doorn, Claudia Turner
BACKGROUND: Central nervous system (CNS) infections are an important cause of childhood morbidity and mortality. The aetiologies of these potentially vaccine-preventable infections have not been well established in Cambodia. METHODS: We did a one year prospective study of children hospitalised with suspected CNS infection at Angkor Hospital for Children, Siem Reap. Cerebrospinal fluid specimens (CSF) samples underwent culture, multiplex PCR and serological analysis to identify a range of bacterial and viral pathogens...
December 29, 2017: BMC Infectious Diseases
François Ferron, Lorenzo Subissi, Ana Theresa Silveira De Morais, Nhung Thi Tuyet Le, Marion Sevajol, Laure Gluais, Etienne Decroly, Clemens Vonrhein, Gérard Bricogne, Bruno Canard, Isabelle Imbert
Coronaviruses (CoVs) stand out among RNA viruses because of their unusually large genomes (∼30 kb) associated with low mutation rates. CoVs code for nsp14, a bifunctional enzyme carrying RNA cap guanine N7-methyltransferase (MTase) and 3'-5' exoribonuclease (ExoN) activities. ExoN excises nucleotide mismatches at the RNA 3'-end in vitro, and its inactivation in vivo jeopardizes viral genetic stability. Here, we demonstrate for severe acute respiratory syndrome (SARS)-CoV an RNA synthesis and proofreading pathway through association of nsp14 with the low-fidelity nsp12 viral RNA polymerase...
January 9, 2018: Proceedings of the National Academy of Sciences of the United States of America
Jean Kaoru Millet, Gary R Whittaker
During viral entry, enveloped viruses require the fusion of their lipid envelope with host cell membranes. For coronaviruses, this critical step is governed by the virally-encoded spike (S) protein, a class I viral fusion protein that has several unique features. Coronavirus entry is unusual in that it is often biphasic in nature, and can occur at or near the cell surface or in late endosomes. Recent advances in structural, biochemical and molecular biology of the coronavirus S protein has shed light on the intricacies of coronavirus entry, in particular the molecular triggers of coronavirus S-mediated membrane fusion...
December 21, 2017: Virology
Renqiang Liu, Jinliang Wang, Yu Shao, Xijun Wang, Huilei Zhang, Lei Shuai, Jinying Ge, Zhiyuan Wen, Zhigao Bu
Middle East respiratory syndrome coronavirus (MERS-CoV) has been a highly threatening zoonotic pathogen since its outbreak in 2012. Similar to SARS-CoV, MERS-CoV belongs to the coronavirus family and can induce severe respiratory symptoms in humans, with an average case fatality rate of 35% according to the World Health Organization. Spike (S) protein of MERS-CoV is immunogenic and can induce neutralizing antibodies, thus is a potential major target for vaccine development. Here we constructed a chimeric virus based on the vesicular stomatitis virus (VSV) in which the G gene was replaced by MERS-CoV S gene (VSVΔG-MERS)...
December 12, 2017: Antiviral Research
Zhou Shen, Gang Ye, Feng Deng, Gang Wang, Min Cui, Liurong Fang, Shaobo Xiao, Zhen F Fu, Guiqing Peng
Porcine epidemic diarrhea virus (PEDV), an enteropathogenic Alphacoronavirus, has caused enormous economic losses in the pork industry. The non-structural protein 1 (nsp1) is a characteristic feature of Alpha- and Beltacoronaviruses, which exhibits both functional conservation and mechanistic diversity in inhibiting host gene expression and antiviral responses. However, the detailed structure and molecular mechanisms underlying the Alphacoronavirus nsp1 inhibition of host gene expression remain unclear. Here, we report the first full-length crystal structure of Alphacoronavirus nsp1 from PEDV...
December 13, 2017: Journal of Virology
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