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structural basis and functional analysis of the sars coronavirus nsp14-nsp10 complex.nonstructural protein 14 (nsp14) of coronaviruses (cov) is important for viral replication and transcription. the n-terminal exoribonuclease (exon) domain plays a proofreading role for prevention of lethal mutagenesis, and the c-terminal domain functions as a (guanine-n7) methyl transferase (n7-mtase) for mrna capping. the molecular basis of both these functions is unknown. here, we describe crystal structures of severe acute respiratory syndrome (sars)-cov nsp14 in complex with its activator no ...201526159422
contrasted patterns of variation and evolutionary convergence at the antiviral oas1 gene in old world primates.the oligoadenylate synthetase 1 (oas1) enzyme acts as an innate sensor of viral infection and plays a major role in the defense against a wide diversity of viruses. polymorphisms at oas1 have been shown to correlate with differential susceptibility to several infections of great public health significance, including hepatitis c virus, sars coronavirus, and west nile virus. population genetics analyses in hominoids have revealed interesting evolutionary patterns. in central african chimpanzee, oa ...201526156123
contrasted patterns of variation and evolutionary convergence at the antiviral oas1 gene in old world primates.the oligoadenylate synthetase 1 (oas1) enzyme acts as an innate sensor of viral infection and plays a major role in the defense against a wide diversity of viruses. polymorphisms at oas1 have been shown to correlate with differential susceptibility to several infections of great public health significance, including hepatitis c virus, sars coronavirus, and west nile virus. population genetics analyses in hominoids have revealed interesting evolutionary patterns. in central african chimpanzee, oa ...201526156123
a g-quadruplex-binding macrodomain within the "sars-unique domain" is essential for the activity of the sars-coronavirus replication-transcription complex.the multi-domain non-structural protein 3 of sars-coronavirus is a component of the viral replication/transcription complex (rtc). among other domains, it contains three sequentially arranged macrodomains: the x domain and subdomains sud-n as well as sud-m within the "sars-unique domain". the x domain was proposed to be an adp-ribose-1"-phosphatase or a poly(adp-ribose)-binding protein, whereas sud-nm binds oligo(g)-nucleotides capable of forming g-quadruplexes. here, we describe the application ...201526149721
the role of c5a in acute lung injury induced by highly pathogenic viral infections.the complement system, an important part of innate immunity, plays a critical role in pathogen clearance. unregulated complement activation is likely to play a crucial role in the pathogenesis of acute lung injury (ali) induced by highly pathogenic virus including influenza a viruses h5n1, h7n9, and severe acute respiratory syndrome (sars) coronavirus. in highly pathogenic virus-induced acute lung diseases, high levels of chemotactic and anaphylatoxic c5a were produced as a result of excessive c ...201526060601
understanding the t cell immune response in sars coronavirus infection.the severe acute respiratory syndrome (sars) epidemic started in late 2002 and swiftly spread across 5 continents with a mortality rate of around 10%. although the epidemic was eventually controlled through the implementation of strict quarantine measures, there continues a need to investigate the sars coronavirus (sars-cov) and develop interventions should it re-emerge. numerous studies have shown that neutralizing antibodies against the virus can be found in patients infected with sars-cov wit ...201226038429
bats as reservoirs of severe emerging infectious diseases.in recent years severe infectious diseases have been constantly emerging, causing panic in the world. now we know that many of these terrible diseases are caused by viruses originated from bats (table 1), such as ebola virus, marburg, sars coronavirus (sars-cov), mers coronavirus (mers-cov), nipah virus (niv) and hendra virus (hev). these viruses have co-evolved with bats due to bats' special social, biological and immunological features. although bats are not in close contact with humans, spill ...201525997928
transcriptome profiling of the virus-induced innate immune response in pteropus vampyrus and its attenuation by nipah virus interferon antagonist functions.bats are important reservoirs for several viruses, many of which cause lethal infections in humans but have reduced pathogenicity in bats. as the innate immune response is critical for controlling viruses, the nature of this response in bats and how it may differ from that in other mammals are of great interest. using next-generation transcriptome sequencing (mrna-seq), we profiled the transcriptional response of pteropus vampyrus bat kidney (pvk) cells to newcastle disease virus (ndv), an avian ...201525972557
development of animal models against emerging coronaviruses: from sars to mers coronavirus.two novel coronaviruses have emerged to cause severe disease in humans. while bats may be the primary reservoir for both viruses, sars coronavirus (sars-cov) likely crossed into humans from civets in china, and mers coronavirus (mers-cov) has been transmitted from camels in the middle east. unlike sars-cov that resolved within a year, continued introductions of mers-cov present an on-going public health threat. animal models are needed to evaluate countermeasures against emerging viruses. with s ...201525791336
vhl negatively regulates sars coronavirus replication by modulating nsp16 ubiquitination and stability.eukaryotic cellular and most viral rnas carry a 5'-terminal cap structure, a 5'-5' triphosphate linkage between the 5' end of the rna and a guanosine nucleotide (cap-0). sars coronavirus (sars-cov) nonstructural protein nsp16 functions as a methyltransferase, to methylate mrna cap-0 structure at the ribose 2'-o position of the first nucleotide to form cap-1 structures. however, whether there is interplay between nsp16 and host proteins was not yet clear. in this report, we identified several pot ...201525732088
coronaviruses: an overview of their replication and pathogenesis.coronaviruses (covs), enveloped positive-sense rna viruses, are characterized by club-like spikes that project from their surface, an unusually large rna genome, and a unique replication strategy. coronaviruses cause a variety of diseases in mammals and birds ranging from enteritis in cows and pigs and upper respiratory disease in chickens to potentially lethal human respiratory infections. here we provide a brief introduction to coronaviruses discussing their replication and pathogenicity, and ...201525720466
analysis of cathepsin and furin proteolytic enzymes involved in viral fusion protein activation in cells of the bat reservoir host.bats of different species play a major role in the emergence and transmission of highly pathogenic viruses including ebola virus, sars-like coronavirus and the henipaviruses. these viruses require proteolytic activation of surface envelope glycoproteins needed for entry, and cellular cathepsins have been shown to be involved in proteolysis of glycoproteins from these distinct virus families. very little is currently known about the available proteases in bats. to determine whether the utilizatio ...201525706132
protease inhibitors targeting coronavirus and filovirus entry.in order to gain entry into cells, diverse viruses, including ebola virus, sars-coronavirus and the emerging mers-coronavirus, depend on activation of their envelope glycoproteins by host cell proteases. the respective enzymes are thus excellent targets for antiviral intervention. in cell culture, activation of ebola virus, as well as sars- and mers-coronavirus can be accomplished by the endosomal cysteine proteases, cathepsin l (ctsl) and cathepsin b (ctsb). in addition, sars- and mers-coronavi ...201525666761
detection of coronavirus genomes in moluccan naked-backed fruit bats in indonesia.bats have been shown to serve as natural reservoirs for numerous emerging viruses including severe acute respiratory syndrome coronavirus (sars-cov). in the present study, we report the discovery of bat cov genes in indonesian moluccan naked-backed fruit bats (dobsonia moluccensis). a partial rna-dependent rna polymerase gene sequence was detected in feces and tissues samples from the fruit bats, and the region between the rdrp and helicase genes could also be amplified from fecal samples. phylo ...201525643817
ifitm-family proteins: the cell's first line of antiviral defense.animal cells use a wide variety of mechanisms to slow or prevent replication of viruses. these mechanisms are usually mediated by antiviral proteins whose expression and activities can be constitutive but are frequently amplified by interferon induction. among these interferon-stimulated proteins, members of the ifitm (interferon-induced transmembrane) family are unique because they prevent infection before a virus can traverse the lipid bilayer of the cell. at least three human ifitm proteins-i ...025599080
the sars-coronavirus papain-like protease: structure, function and inhibition by designed antiviral compounds.over 10 years have passed since the deadly human coronavirus that causes severe acute respiratory syndrome (sars-cov) emerged from the guangdong province of china. despite the fact that the sars-cov pandemic infected over 8500 individuals, claimed over 800 lives and cost billions of dollars in economic loss worldwide, there still are no clinically approved antiviral drugs, vaccines or monoclonal antibody therapies to treat sars-cov infections. the recent emergence of the deadly human coronavirus ...201525554382
the sars coronavirus papain like protease can inhibit irf3 at a post activation step that requires deubiquitination activity.the outcome of a viral infection is regulated by complex interactions of viral and host factors. sars coronavirus (sars-cov) engages and regulates several innate immune response pathways during infection. we have previously shown that the sars-cov papain-like protease (plpro) inhibits type i interferon (ifn) by inhibiting irf3 phosphorylation thereby blocking downstream interferon induction. this finding prompted us to identify other potential mechanisms of inhibition of plpro on ifn induction.201425481026
novel respiratory viruses: what should the clinician be alert for?since 1990, several novel respiratory viruses affecting humans have been described. in this review, we focus on three pathogens that have caused significant human mortality and raise important public health concerns: severe acute respiratory syndrome (sars)-coronavirus, middle east respiratory syndrome (mers)-coronavirus and avian influenza a viruses (h5n1 and h7n9). novel respiratory viruses have the potential to instil fear in the public and physicians alike if they are associated with a high ...201425468912
genomics and proteomics of mycobacteriophage patience, an accidental tourist in the mycobacterium neighborhood.newly emerging human viruses such as ebola virus, severe acute respiratory syndrome (sars) virus, and hiv likely originate within an extant population of viruses in nonhuman hosts and acquire the ability to infect and cause disease in humans. although several mechanisms preventing viral infection of particular hosts have been described, the mechanisms and constraints on viral host expansion are ill defined. we describe here mycobacteriophage patience, a newly isolated phage recovered using mycob ...201425467442
insights into rna synthesis, capping, and proofreading mechanisms of sars-coronavirus.the successive emergence of highly pathogenic coronaviruses (covs) such as the severe acute respiratory syndrome (sars-cov) in 2003 and the middle east respiratory syndrome coronavirus (mers-cov) in 2012 has stimulated a number of studies on the molecular biology. this research has provided significant new insight into functions and activities of the replication/transcription multi-protein complex. the latter directs both continuous and discontinuous rna synthesis to replicate and transcribe the ...201425451065
acquisition of new protein domains by coronaviruses: analysis of overlapping genes coding for proteins n and 9b in sars coronavirus.acquisition of new proteins by viruses usually occurs through horizontal gene transfer or through gene duplication, but another, less common mechanism is the usage of completely or partially overlapping reading frames. a case of acquisition of a completely new protein through introduction of a start codon in an alternative reading frame is the protein encoded by open reading frame (orf) 9b of sars coronavirus. this gene completely overlaps with the nucleocapsid (n) gene (orf9a). our findings ind ...201525410051
the sars-coronavirus membrane protein induces apoptosis via interfering with pdk1-pkb/akt signalling.a number of viral gene products are capable of inducing apoptosis by interfering with various cellular signalling cascades. we previously reported the pro-apoptotic property of the sars-cov (severe acute respiratory syndrome coronavirus) m (membrane)-protein and a down-regulation of the phosphorylation level of the cell-survival protein pkb (protein kinase b)/akt in cells expressing m-protein. we also showed that overexpression of pdk1 (3-phosphoinositide-dependent protein kinase 1), the immedia ...201425271362
molecular pathology of emerging coronavirus infections.respiratory viruses can cause a wide spectrum of pulmonary diseases, ranging from mild, upper respiratory tract infections to severe and life-threatening lower respiratory tract infections, including the development of acute lung injury (ali) and acute respiratory distress syndrome (ards). viral clearance and subsequent recovery from infection require activation of an effective host immune response; however, many immune effector cells may also cause injury to host tissues. severe acute respirato ...201525270030
substrate specificity and rational design of peptidomimetic inhibitors for sars coronavirus main protease. 201425224113
message in a bottle: lessons learned from antagonism of sting signalling during rna virus infection.sting has emerged in recent years as an important signalling adaptor in the activation of type i interferon responses during infection with dna viruses and bacteria. an increasing body of evidence suggests that sting also modulates responses to rna viruses, though the mechanisms remain less clear. in this review, we give a brief overview of the ways in which sting facilitates sensing of rna viruses. these include modulation of rig-i-dependent responses through sting's interaction with mavs, and ...201425212897
sars-coronavirus open reading frame-9b suppresses innate immunity by targeting mitochondria and the mavs/traf3/traf6 signalosome.coronaviruses (cov) have recently emerged as potentially serious pathogens that can cause significant human morbidity and death. the severe acute respiratory syndrome (sars)-cov was identified as the etiologic agent of the 2002-2003 international sars outbreak. yet, how sars evades innate immune responses to cause human disease remains poorly understood. in this study, we show that a protein encoded by sars-cov designated as open reading frame-9b (orf-9b) localizes to mitochondria and causes mit ...201425135833
the sars coronavirus 3a protein binds calcium in its cytoplasmic domain.the severe acute respiratory syndrome coronavirus (sars-cov) is a positive stranded rna virus with ∼30kb genome. among all open reading frames (orfs) of this virus, the orf3a is the largest, and encodes a protein of 274 amino acids, named as 3a protein. sequence analysis suggests that the orf3a aligned to one calcium pump present in plasmodium falciparum and the enzyme glutamine synthetase found in leptospira interrogans. this sequence similarity was found to be limited only to amino acid residu ...201425116391
[new coronavirus infection: new challenges, new legacies].a new highly pathogenic human coronavirus has emerged. its natural history and its determinants are still under investigation. it lacks a publication to examine all the cases identified worldwide. therefore, the objective of this paper is to describe the cases and deaths caused by the new coronavirus.201725078748
antibody-dependent sars coronavirus infection is mediated by antibodies against spike proteins.the severe acute respiratory syndrome coronavirus (sars-cov) still carries the potential for reemergence, therefore efforts are being made to create a vaccine as a prophylactic strategy for control and prevention. antibody-dependent enhancement (ade) is a mechanism through which dengue viruses, feline coronaviruses, and hiv viruses take advantage of anti-viral humoral immune responses to infect host target cells. here we describe our observations of sars-cov using ade to enhance the infectivity ...201425073113
from sars to mers: crystallographic studies on coronaviral proteases enable antiviral drug design.this review focuses on the important contributions that macromolecular crystallography has made over the past 12 years to elucidating structures and mechanisms of the essential proteases of coronaviruses, the main protease (m(pro) ) and the papain-like protease (pl(pro) ). the role of x-ray crystallography in structure-assisted drug discovery against these targets is discussed. aspects dealt with in this review include the emergence of the sars coronavirus in 2002-2003 and of the mers coronaviru ...201425039866
the effectiveness of convalescent plasma and hyperimmune immunoglobulin for the treatment of severe acute respiratory infections of viral etiology: a systematic review and exploratory meta-analysis.administration of convalescent plasma, serum, or hyperimmune immunoglobulin may be of clinical benefit for treatment of severe acute respiratory infections (saris) of viral etiology. we conducted a systematic review and exploratory meta-analysis to assess the overall evidence.201525030060
substitution at aspartic acid 1128 in the sars coronavirus spike glycoprotein mediates escape from a s2 domain-targeting neutralizing monoclonal antibody.the severe acute respiratory syndrome coronavirus (sars-cov) is the etiological agent for the infectious disease, sars, which first emerged 10 years ago. sars-cov is a zoonotic virus that has crossed the species barriers to infect humans. bats, which harbour a diverse pool of sars-like covs (sl-covs), are believed to be the natural reservoir. the sars-cov surface spike (s) protein is a major antigenic determinant in eliciting neutralizing antibody production during sars-cov infection. in our pre ...201425019613
accessory proteins of sars-cov and other coronaviruses.the huge rna genome of sars coronavirus comprises a number of open reading frames that code for a total of eight accessory proteins. although none of these are essential for virus replication, some appear to have a role in virus pathogenesis. notably, some sars-cov accessory proteins have been shown to modulate the interferon signaling pathways and the production of pro-inflammatory cytokines. the structural information on these proteins is also limited, with only two (p7a and p9b) having their ...201424995382
crystal structure of the papain-like protease of mers coronavirus reveals unusual, potentially druggable active-site features.the middle-east respiratory syndrome coronavirus (mers-cov) causes severe acute pneumonia and renal failure. the mers-cov papain-like protease (pl(pro)) is a potential target for the development of antiviral drugs. to facilitate these efforts, we determined the three-dimensional structure of the enzyme by x-ray crystallography. the molecule consists of a ubiquitin-like domain and a catalytic core domain. the catalytic domain displays an extended right-hand fold with a zinc ribbon and embraces a ...201424992731
sars coronavirus without reservoir originated from an unnatural evolution, experienced the reverse evolution, and finally disappeared in the world. 201424985597
palindromes in sars and other coronaviruses.with the identification of a novel coronavirus associated with the severe acute respiratory syndrome (sars), computational analysis of its rna genome sequence is expected to give useful clues to help elucidate the origin, evolution, and pathogenicity of the virus. in this paper, we study the collective counts of palindromes in the sars genome along with all the completely sequenced coronaviruses. based on a markov-chain model for the genome sequence, the mean and standard deviation for the numbe ...200424966663
development of a single nucleotide polymorphism dna microarray for the detection and genotyping of the sars coronavirus.severe acute respiratory syndrome (sars), a disease that spread widely in the world during late 2002 to 2004, severely threatened public health. although there have been no reported infections since 2004, the extremely pathogenic sars coronavirus (sars-cov), as the causative agent of sars, has recently been identified in animals, showing the potential for the re-emergence of this disease. previous studies showed that 27 single nucleotide polymorphism (snp) mutations among the spike (s) gene of t ...201424950883
genetic manipulation of outer membrane permeability: generating porous heterogeneous catalyst analogs in escherichia coli.the limited permeability of the e. coli outer membrane can significantly hinder whole-cell biocatalyst performance. in this study, the sars coronavirus small envelope protein (scve) was expressed in e. coli cells previously engineered for periplasmic expression of carbonic anhydrase (ca) activity. this maneuver increased small molecule uptake by the cells, resulting in increased apparent ca activity of the biocatalysts. the enhancements in activity were quantified using methods developed for tra ...201424932924
effects of toll-like receptor stimulation on eosinophilic infiltration in lungs of balb/c mice immunized with uv-inactivated severe acute respiratory syndrome-related coronavirus vaccine.severe acute respiratory syndrome-related coronavirus (sars-cov) is an emerging pathogen that causes severe respiratory illness. whole uv-inactivated sars-cov (uv-v), bearing multiple epitopes and proteins, is a candidate vaccine against this virus. however, whole inactivated sars vaccine that includes nucleocapsid protein is reported to induce eosinophilic infiltration in mouse lungs after challenge with live sars-cov. in this study, an ability of toll-like receptor (tlr) agonists to reduce the ...201424850731
screening of an fda-approved compound library identifies four small-molecule inhibitors of middle east respiratory syndrome coronavirus replication in cell culture.coronaviruses can cause respiratory and enteric disease in a wide variety of human and animal hosts. the 2003 outbreak of severe acute respiratory syndrome (sars) first demonstrated the potentially lethal consequences of zoonotic coronavirus infections in humans. in 2012, a similar previously unknown coronavirus emerged, middle east respiratory syndrome coronavirus (mers-cov), thus far causing over 650 laboratory-confirmed infections, with an unexplained steep rise in the number of cases being r ...201424841269
[a novel coronavirus, mers-cov].a novel human coronavirus was identified in saudi arabia and qatar as the causative agent of severe acute respiratory diseases in 2012. the virus was termed middle east respiratory syndrome coronavirus (mers-cov) and is taken notice of important coronavirus caused severe diseases to human after the outbreak of severe acute respiratory syndrome (sars) coronavirus. there is a lot of unknown characterization regarding mers-cov because of less than one year after finding the first case. mers-cov was ...201324769571
the yxxφ motif within the severe acute respiratory syndrome coronavirus (sars-cov) 3a protein is crucial for its intracellular transport.the sars coronavirus (sars-cov) 3a protein functions as an ion channel, induces apoptosis and is important for viral pathogenesis. it is expressed on the cell surface and contains a tyrosine-based sorting motif and a di-acidic motif, which may be crucial for its intracellular trafficking. however the role of these motifs is not fully understood in the case of 3a protein.201424762043
phagocytic cells contribute to the antibody-mediated elimination of pulmonary-infected sars coronavirus.while the 2002-2003 outbreak of severe acute respiratory syndrome (sars) resulted in 774 deaths, patients who were affected with mild pulmonary symptoms successfully recovered. the objective of the present work was to identify, using sars coronavirus (sars-cov) mouse infection models, immune factors responsible for clearing of the virus. the elimination of pulmonary sars-cov infection required the activation of b cells by cd4(+) t cells. furthermore, passive immunization (post-infection) with ho ...201424725942
prevention and treatment of viral respiratory infections by traditional chinese herbs.this review focuses on current knowledge of traditional chinese herbs on prevention and treatment of viral respiratory infections, especially caused by severe acute respiratory syndromes (sars) virus, respiratory syncytial virus (rsv) and influenza viruses.201424709192
outcomes of sars survivors in china: not only physical and psychiatric co-morbidities.the year 2013 marks the 10th anniversary of the outbreak of the severe acute respiratory syndrome (sars). we present a comprehensive introduction to the current situation of surviving sars victims in china where the disease originated and spread across the world 10 years ago.201424676486
serological assays for emerging coronaviruses: challenges and pitfalls.more than a decade after the emergence of severe acute respiratory syndrome coronavirus (sars-cov) in 2002/2003 the occurrence of a novel cov termed middle east respiratory syndrome (mers) cov challenges researchers and public health authorities. to control spread and finally contain novel viruses, rapid identification and subsequent isolation of infected individuals and their contacts is of utmost importance. next to methods for nucleic acid detection, validated serological assays are particula ...201424670324
multi-organ lesions in suckling mice infected with sars-associated mammalian reovirus linked with apoptosis induced by viral proteins μ1 and σ1.we reported the isolation and characterization of a novel mammalian reassortant reovirus byd1 that may have played an accomplice role with sars-coronavirus during the 2003 sars pandemic. the pathogenic mechanism of this novel reovirus is unknown. reovirus pathogenicity has been associated with virus-induced apoptosis in cultured cells and in vivo. the reovirus outer capsid protein μ1 is recognized as the primary determinant of reovirus-induced apoptosis. here, we investigated the apoptosis induc ...201424664247
how change of public transportation usage reveals fear of the sars virus in a city.the outbreaks of the severe acute respiratory syndrome (sars) epidemic in 2003 resulted in unprecedented impacts on people's daily life. one of the most significant impacts to people is the fear of contacting the sars virus while engaging daily routine activity. here we use data from daily underground ridership in taipei city and daily reported new sars cases in taiwan to model the dynamics of the public fear of the sars virus during the wax and wane of the sars period. we found that for each re ...201424647278
severe acute respiratory syndrome-coronavirus infection in aged nonhuman primates is associated with modulated pulmonary and systemic immune responses.many respiratory viruses disproportionately impact the elderly. likewise, advanced age correlated with more adverse disease outcomes following severe acute respiratory syndrome coronavirus (sars-cov) infection in humans. we used an aged african green monkey sars-cov infection model to better understand age-related mechanisms of increased susceptibility to viral respiratory infections. nonhuman primates are critical translational models for such research given their similarities to humans in immu ...201424642138
sars coronavirus papain-like protease inhibits the type i interferon signaling pathway through interaction with the sting-traf3-tbk1 complex.sars coronavirus (sars-cov) develops an antagonistic mechanism by which to evade the antiviral activities of interferon (ifn). previous studies suggested that sars-cov papain-like protease (plpro) inhibits activation of the irf3 pathway, which would normally elicit a robust ifn response, but the mechanism(s) used by sars plpro to inhibit activation of the irf3 pathway is not fully known. in this study, we uncovered a novel mechanism that may explain how sars plpro efficiently inhibits activation ...201424622840
protection from sars coronavirus conferred by live measles vaccine expressing the spike glycoprotein.the recent identification of a novel human coronavirus responsible of a sars-like illness in the middle-east a decade after the sars pandemic, demonstrates that reemergence of a sars-like coronavirus from an animal reservoir remains a credible threat. because sars is contracted by aerosolized contamination of the respiratory tract, a vaccine inducing mucosal long-term protection would be an asset to control new epidemics. to this aim, we generated live attenuated recombinant measles vaccine (mv) ...201424606680
the pathology and pathogenesis of experimental severe acute respiratory syndrome and influenza in animal models.respiratory viruses that emerge in the human population may cause high morbidity and mortality, as well as concern about pandemic spread. examples are severe acute respiratory syndrome coronavirus (sars-cov) and novel variants of influenza a virus, such as h5n1 and pandemic h1n1. different animal models are used to develop therapeutic and preventive measures against such viruses, but it is not clear which are most suitable. therefore, this review compares animal models of sars and influenza, wit ...201424581932
x-ray structural and biological evaluation of a series of potent and highly selective inhibitors of human coronavirus papain-like proteases.structure-guided design was used to generate a series of noncovalent inhibitors with nanomolar potency against the papain-like protease (plpro) from the sars coronavirus (cov). a number of inhibitors exhibit antiviral activity against sars-cov infected vero e6 cells and broadened specificity toward the homologous plp2 enzyme from the human coronavirus nl63. selectivity and cytotoxicity studies established a more than 100-fold preference for the coronaviral enzyme over homologous human deubiquiti ...201424568342
human coronavirus nl63 replication is cyclophilin a-dependent and inhibited by non-immunosuppressive cyclosporine a-derivatives including alisporivir.until recently, there were no effective drugs available blocking coronavirus (cov) infection in humans and animals. we have shown before that csa and fk506 inhibit coronavirus replication (carbajo-lozoya, j., müller, m.a., kallies, s., thiel, v., drosten, c., von brunn, a. replication of human coronaviruses sars-cov, hcov-nl63 and hcov-229e is inhibited by the drug fk506. virus res. 2012; pfefferle, s., schöpf, j., kögl, m., friedel, c., müller, m.a., stellberger, t., von dall'armi, e., herzog, ...201424566223
yeast-based assays for the high-throughput screening of inhibitors of coronavirus rna cap guanine-n7-methyltransferase.the 5'-cap structure is a distinct feature of eukaryotic mrnas and is important for rna stability and protein translation by providing a molecular signature for the distinction of self or non-self mrna. eukaryotic viruses generally modify the 5'-end of their rnas to mimic the cellular mrna structure, thereby facilitating viral replication in host cells. however, the molecular organization and biochemical mechanisms of the viral capping apparatus typically differ from its cellular counterpart, wh ...201424530452
[anti-virus research of triterpenoids in licorice].licorice is a leguminous plant of glycyrrhiza. it is a traditional chinese herbal medicine. triterpenoid is one of the mainly active components of licorice. in recent years, the broad-spectrum antiviral activity of many triterpenoids in licorice was confirmed, and these findings have become a hot spot of antiviral immunity. the triterpenoids of licorice has the potential to become a novel broad-spectrum antiviral medicine and will be widely used in the clinical treatment. this review provided a ...201324520776
influence of hydrophobic and electrostatic residues on sars-coronavirus s2 protein stability: insights into mechanisms of general viral fusion and inhibitor design.severe acute respiratory syndrome (sars) is an acute respiratory disease caused by the sars-coronavirus (sars-cov). sars-cov entry is facilitated by the spike protein (s), which consists of an n-terminal domain (s1) responsible for cellular attachment and a c-terminal domain (s2) that mediates viral and host cell membrane fusion. the sars-cov s2 is a potential drug target, as peptidomimetics against s2 act as potent fusion inhibitors. in this study, site-directed mutagenesis and thermal stabilit ...201424519901
[bats, viruses and humans: coronaviruses on the rise?].the outbreak of the sars coronavirus in 2002/2003 and the recent disease cases with a new human coronavirus (originally designated emc-cov, recently renamed mers-cov) have put the focus onto the virus family coronaviridae. both viruses appeared to have managed to jump over the species barrier from a bat reservoir to the human population. bats are considered to serve as a natural reservoir for coronaviruses infecting mammals. an important factor for crossing the species-barrier is the adaptation ...201424511826
suppression of innate antiviral response by severe acute respiratory syndrome coronavirus m protein is mediated through the first transmembrane domain.coronaviruses have developed various measures to evade innate immunity. we have previously shown that severe acute respiratory syndrome (sars) coronavirus m protein suppresses type i interferon (ifn) production by impeding the formation of functional traf3-containing complex. in this study, we demonstrate that the ifn-antagonizing activity is specific to sars coronavirus m protein and is mediated through its first transmembrane domain (tm1) located at the n terminus. m protein from human coronav ...201424509444
kaempferol derivatives as antiviral drugs against the 3a channel protein of coronavirus.the protein coded by the open-reading-frame 3a of sars coronavirus has been demonstrated to form a cation-selective channel that may become expressed in the infected cell. the activity of the channel is involved in the mechanism of virus release. drugs that inhibit the ion channel can, therefore, inhibit virus release, and they could be a source for development of novel therapeutic antiviral agents. various drugs found in chinese herbs that are well known as anticancer agents also have an antivi ...201424458263
anti-frameshifting ligand reduces the conformational plasticity of the sars virus pseudoknot.programmed -1 ribosomal frameshifting (-1 prf) stimulated by mrna pseudoknots regulates gene expression in many viruses, making pseudoknots potential targets for anti-viral drugs. the mechanism by which pseudoknots trigger -1 prf, however, remains controversial, with several competing models. recent work showed that high -1 prf efficiency was linked to high pseudoknot conformational plasticity via the formation of alternate conformers. we tested whether pseudoknots bound with an anti-frameshifti ...201424446874
the sars coronavirus nucleocapsid protein--forms and functions.the nucleocapsid phosphoprotein of the severe acute respiratory syndrome coronavirus (sars-cov n protein) packages the viral genome into a helical ribonucleocapsid (rnp) and plays a fundamental role during viral self-assembly. it is a protein with multifarious activities. in this article we will review our current understanding of the n protein structure and its interaction with nucleic acid. highlights of the progresses include uncovering the modular organization, determining the structures of ...201424418573
comparative analysis of the activation of unfolded protein response by spike proteins of severe acute respiratory syndrome coronavirus and human coronavirus hku1.whereas severe acute respiratory syndrome (sars) coronavirus (sars-cov) is associated with severe disease, human coronavirus hku1 (hcov-hku1) commonly circulates in the human populations causing generally milder illness. spike (s) protein of sars-cov activates the unfolded protein response (upr). it is not understood whether hcov-hku1 s protein has similar activity. in addition, the upr-activating domain in sars-cov s protein remains to be identified.201424410900
inhibition of human neutrophil elastase by pentacyclic triterpenes.inhibiting human neutrophil elastase (hne) is a promising strategy for treating inflammatory lung diseases, such as h1n1 and sars virus infections. the use of sivelestat, the only clinically registered synthesized hne inhibitor, is largely limited by its risk of organ toxicity because it irreversibly inhibits hne. therefore, potent reversible hne inhibitors are promising alternatives to sivelestat.201324376583
in-vitro renal epithelial cell infection reveals a viral kidney tropism as a potential mechanism for acute renal failure during middle east respiratory syndrome (mers) coronavirus infection.the middle east respiratory syndrome coronavirus (mers-cov) causes symptoms similar to severe acute respiratory syndrome coronavirus (sars-cov), yet involving an additional component of acute renal failure (arf) according to several published case reports. impairment of the kidney is not typically seen in coronavirus infections. the role of kidney infection in mers is not understood.201324364985
yeast-expressed recombinant protein of the receptor-binding domain in sars-cov spike protein with deglycosylated forms as a sars vaccine candidate.development of vaccines for preventing a future pandemic of severe acute respiratory syndrome (sars) caused by sars coronavirus (sars-cov) and for biodefense preparedness is urgently needed. our previous studies have shown that a candidate sars vaccine antigen consisting of the receptor-binding domain (rbd) of sars-cov spike protein can induce potent neutralizing antibody responses and protection against sars-cov challenge in vaccinated animals. to optimize expression conditions for scale-up pro ...201424355931
atlas of coronavirus replicase structure.the international response to sars-cov has produced an outstanding number of protein structures in a very short time. this review summarizes the findings of functional and structural studies including those derived from cryoelectron microscopy, small angle x-ray scattering, nmr spectroscopy, and x-ray crystallography, and incorporates bioinformatics predictions where no structural data is available. structures that shed light on the function and biological roles of the proteins in viral replicat ...201424355834
severe acute respiratory syndrome beyond amoy gardens: completing the incomplete legacy.the temporal and spatial distributions of the 2003 severe acute respiratory syndrome (sars) outbreak in amoy gardens of hong kong was reexamined using all confirmed cases. the outbreak actually extended to nearby residential complexes. airborne spread was the most likely explanation, and the sars coronavirus could have spread over a distance of 200 m.201424319085
viral subversion of nucleocytoplasmic trafficking.trafficking of proteins and rna into and out of the nucleus occurs through the nuclear pore complex (npc). because of its critical function in many cellular processes, the npc and transport factors are common targets of several viruses that disrupt key constituents of the machinery to facilitate viral replication. many viruses such as poliovirus and severe acute respiratory syndrome (sars) virus inhibit protein import into the nucleus, whereas viruses such as influenza a virus target and disrupt ...201324289861
sars-cov orf1b-encoded nonstructural proteins 12-16: replicative enzymes as antiviral targets.the sars (severe acute respiratory syndrome) pandemic caused ten years ago by the sars-coronavirus (sars-cov) has stimulated a number of studies on the molecular biology of coronaviruses. this research has provided significant new insight into many mechanisms used by the coronavirus replication-transcription complex (rtc). the rtc directs and coordinates processes in order to replicate and transcribe the coronavirus genome, a single-stranded, positive-sense rna of outstanding length (∼27-32kilob ...201424269475
respiratory virus detection: beyond influenza and rsv into emerging infectious diseases.in the era of global travel, clinicians can no longer consider just influenza and respiratory synctial virus (rsv) and ignore other causes of presumptive viral respiratory tract infections. since the recognition of severe acute respiratory syndrome (sars) coronavirus in 2003, novel viruses seem to emerge more frequently. novel influenza strains, the novel coronavirus (mers-cov) identified last year in the middle east, other novel viruses, and increasing numbers of immunocompromised patients that ...201324261155
severe acute respiratory syndrome (sars) coronavirus: possible re-emergence of the asian-global novel threat. 201324260834
bats as animal reservoirs for the sars coronavirus: hypothesis proved after 10 years of virus hunting. 201324174406
characterization of a novel betacoronavirus related to middle east respiratory syndrome coronavirus in european hedgehogs.bats are known to host viruses closely related to important human coronaviruses (hcovs), such as hcov-229e, severe-acute respiratory syndrome coronavirus (sars-cov), and middle east respiratory syndrome cov (mers-cov). as rna viruses may coevolve with their hosts, we sought to investigate the closest sister taxon to bats, the eulipotyphla, and screened european hedgehogs (erinaceus europaeus) from germany for cov by nested reverse transcriptase pcr. a novel betacoronavirus species in a phylogene ...201424131722
feature selection methods for identifying genetic determinants of host species in rna viruses.despite environmental, social and ecological dependencies, emergence of zoonotic viruses in human populations is clearly also affected by genetic factors which determine cross-species transmission potential. rna viruses pose an interesting case study given their mutation rates are orders of magnitude higher than any other pathogen--as reflected by the recent emergence of sars and influenza for example. here, we show how feature selection techniques can be used to reliably classify viral sequence ...201324130470
proteolytic activation of the sars-coronavirus spike protein: cutting enzymes at the cutting edge of antiviral research.the severe acute respiratory syndrome (sars) pandemic revealed that zoonotic transmission of animal coronaviruses (cov) to humans poses a significant threat to public health and warrants surveillance and the development of countermeasures. the activity of host cell proteases, which cleave and activate the sars-cov spike (s) protein, is essential for viral infectivity and constitutes a target for intervention. however, the identities of the proteases involved have been unclear. pioneer studies id ...201324121034
active replication of middle east respiratory syndrome coronavirus and aberrant induction of inflammatory cytokines and chemokines in human macrophages: implications for pathogenesis.middle east respiratory syndrome coronavirus (mers-cov) infection caused severe pneumonia and multiorgan dysfunction and had a higher crude fatality rate (around 50% vs. 10%) than sars coronavirus (sars-cov) infection. to understand the pathogenesis, we studied viral replication, cytokine/chemokine response, and antigen presentation in mers-cov-infected human monocyte-derived macrophages (mdms) versus sars-cov-infected mdms. only mers-cov can replicate in mdms. both viruses were unable to signif ...201424065148
differential sensitivity of bat cells to infection by enveloped rna viruses: coronaviruses, paramyxoviruses, filoviruses, and influenza viruses.bats (chiroptera) host major human pathogenic viruses including corona-, paramyxo, rhabdo- and filoviruses. we analyzed six different cell lines from either yinpterochiroptera (including african flying foxes and a rhinolophid bat) or yangochiroptera (genera carollia and tadarida) for susceptibility to infection by different enveloped rna viruses. none of the cells were sensitive to infection by transmissible gastroenteritis virus (tgev), a porcine coronavirus, or to infection mediated by the spi ...201324023659
the antiviral activity of poly-γ-glutamic acid, a polypeptide secreted by bacillus sp., through induction of cd14-dependent type i interferon responses.poly-γ-glutamic acid (γ-pga) is an anionic polypeptide secreted by bacillus sp. that has been shown to activate immune cells through interactions with toll-like receptor 4 (tlr4). however, its ability to induce the type i interferon (ifn) response has not yet been characterized. here, we demonstrate that γ-pga induces type i ifn signaling pathway via the tlr4 signaling pathway. the induction required both myeloid differentiation factor 2 (md2) and the pattern-recognition receptor cd14, which are ...201324016850
receptor recognition and cross-species infections of sars coronavirus.receptor recognition is a major determinant of the host range, cross-species infections, and pathogenesis of the severe acute respiratory syndrome coronavirus (sars-cov). a defined receptor-binding domain (rbd) in the sars-cov spike protein specifically recognizes its host receptor, angiotensin-converting enzyme 2 (ace2). this article reviews the latest knowledge about how rbds from different sars-cov strains interact with ace2 from several animal species. detailed research on these rbd/ace2 int ...201323994189
therapeutic options for middle east respiratory syndrome coronavirus (mers-cov)--possible lessons from a systematic review of sars-cov therapy.the middle east respiratory syndrome coronavirus (mers-cov) has been detected in a number of countries in the middle east and europe with an apparently high mortality rate. it is phylogenetically related to the sars coronavirus and has also been associated with severe respiratory illness as well as nosocomial transmission in healthcare settings. current international recommendations do not support any specific therapies; however, there are a number of agents, which were used during the sars epid ...201323993766
receptor-binding domain as a target for developing sars vaccines.a decade ago, severe acute respiratory syndrome (sars) coronavirus (sars-cov) caused a global pandemic with a mortality rate of 10%. reports of recent outbreaks of a sars-like disease caused by middle east respiratory syndrome coronavirus (mers-cov) have raised serious concerns of a possible reemergence of sars-cov, either by laboratory escape or the presence of a natural reservoir. therefore, the development of effective and safe sars vaccines is still needed. based on our previous studies, we ...201323977435
severe acute respiratory syndrome (sars): lessons learnt in hong kong.many healthcare workers were infected while looking after the sars patients on the medical wards in 2003. the high infectivity of the sars coronavirus with peak viral load on day 10 of illness when patients were ill, overcrowding of the old medical wards with low air changes/hr (ach), and aerosol-generating procedures while resuscitating the patients were the major factors. procedures reported to present an increased risk of sars transmission include tracheal intubation, non-invasive ventilation ...201323977432
tracing the sars-coronavirus.four coronaviruses (hcov-229e, hcov-oc43, hcov-nl63, hcov-hku1) are endemic in humans and mainly associated with mild respiratory illnesses; whereas the other two coronaviruses [severe acute respiratory syndrome coronavirus (sars-cov) and middle east respiratory syndrome coronavirus (mers-cov)] present as emerging infections causing severe respiratory syndrome. coronaviruses evolve by accumulation of point mutations and recombination of genomes among different strains or species. mammalian coron ...201323977431
tracing the sars-coronavirus.four coronaviruses (hcov-229e, hcov-oc43, hcov-nl63, hcov-hku1) are endemic in humans and mainly associated with mild respiratory illnesses; whereas the other two coronaviruses [severe acute respiratory syndrome coronavirus (sars-cov) and middle east respiratory syndrome coronavirus (mers-cov)] present as emerging infections causing severe respiratory syndrome. coronaviruses evolve by accumulation of point mutations and recombination of genomes among different strains or species. mammalian coron ...201323977431
from sars coronavirus to novel animal and human coronaviruses.in 2003, severe acute respiratory syndrome coronavirus (sars-cov) caused one of the most devastating epidemics known to the developed world. there were two important lessons from this epidemic. firstly, coronaviruses, in addition to influenza viruses, can cause severe and rapidly spreading human infections. secondly, bats can serve as the origin and natural animal reservoir of deadly human viruses. since then, researchers around the world, especially those in asia where sars-cov was first identi ...201323977429
metagenomic analysis of the ferret fecal viral flora.ferrets are widely used as a small animal model for a number of viral infections, including influenza a virus and sars coronavirus. to further analyze the microbiological status of ferrets, their fecal viral flora was studied using a metagenomics approach. novel viruses from the families picorna-, papilloma-, and anelloviridae as well as known viruses from the families astro-, corona-, parvo-, and hepeviridae were identified in different ferret cohorts. ferret kobu- and hepatitis e virus were ma ...201323977082
ace2 - from the renin-angiotensin system to gut microbiota and malnutrition.the renin-angiotensin system (ras) is a complex network that regulates blood pressure, electrolyte and fluid homeostasis, as well as the function of several organs. angiotensin-converting enzyme 2 (ace2) was identified as an enzyme that negatively regulates the ras by converting ang ii, the main bioactive molecule of the ras, to ang 1-7. thus, ace2 counteracts the role of angiotensin-converting enzyme (ace) which generates ang ii from ang i. ace and ace2 have been implicated in several pathologi ...201323962453
severe acute respiratory syndrome coronavirus nonstructural proteins 3, 4, and 6 induce double-membrane vesicles.coronaviruses (cov), like other positive-stranded rna viruses, redirect and rearrange host cell membranes for use as part of the viral genome replication and transcription machinery. specifically, coronaviruses induce the formation of double-membrane vesicles in infected cells. although these double-membrane vesicles have been well characterized, the mechanism behind their formation remains unclear, including which viral proteins are responsible. here, we use transfection of plasmid constructs e ...201323943763
viral pathogens and acute lung injury: investigations inspired by the sars epidemic and the 2009 h1n1 influenza pandemic.acute viral pneumonia is an important cause of acute lung injury (ali), although not enough is known about the exact incidence of viral infection in ali. polymerase chain reaction-based assays, direct fluorescent antigen (dfa) assays, and viral cultures can detect viruses in samples from the human respiratory tract, but the presence of the virus does not prove it to be a pathogen, nor does it give information regarding the interaction of viruses with the host immune response and bacterial flora ...201323934716
middle east respiratory syndrome coronavirus neutralising serum antibodies in dromedary camels: a comparative serological study.a new betacoronavirus-middle east respiratory syndrome coronavirus (mers-cov)-has been identified in patients with severe acute respiratory infection. although related viruses infect bats, molecular clock analyses have been unable to identify direct ancestors of mers-cov. anecdotal exposure histories suggest that patients had been in contact with dromedary camels or goats. we investigated possible animal reservoirs of mers-cov by assessing specific serum antibodies in livestock.201323933067
new strategy for virus discovery: viruses identified in human feces in the last decade.emerging and re-emerging viruses continue to surface all over the world. some of these viruses have the potential for rapid and global spread with high morbidity and mortality, such as the sars coronavirus outbreak. it is extremely urgent and important to identify a novel virus near-instantaneously to develop an active preventive and/or control strategy. as a culture-independent approach, viral metagenomics has been widely used to investigate highly divergent and completely new viruses in humans ...201323917840
the replication of a mouse adapted sars-cov in a mouse cell line stably expressing the murine sars-cov receptor mace2 efficiently induces the expression of proinflammatory cytokines.infection of conventional mice with a mouse adapted (ma15) severe acute respiratory syndrome (sars) coronavirus (cov) reproduces many aspects of human sars such as pathological changes in lung, viremia, neutrophilia, and lethality. however, established mouse cell lines highly susceptible to mouse-adapted sars-cov infection are not available. in this work, efficiently transfectable mouse cell lines stably expressing the murine sars-cov receptor angiotensin converting enzyme 2 (ace2) have been gen ...201323911968
anti-sars coronavirus agents: a patent review (2008 - present).a novel coronavirus (cov), unlike previous typical human coronaviruses (hcovs), was identified as causative agent for severe acute respiratory syndrome (sars). sars first surfaced as a pandemic in late 2002 and originated in southern china. sars-cov rapidly spread to > 30 countries by 2003, infecting nearly 8,000 people and causing around 800 fatalities. after 10 years of silence, a 2012 report alarmed researchers about the emergence of a new strain of cov causing sars-like disease.201323905913
infection prevention and control measures for acute respiratory infections in healthcare settings: an update.viruses account for the majority of the acute respiratory tract infections (aris) globally with a mortality exceeding 4 million deaths per year. the most commonly encountered viruses, in order of frequency, include influenza, respiratory syncytial virus, parainfluenza and adenovirus. current evidence suggests that the major mode of transmission of arls is through large droplets, but transmission through contact (including hand contamination with subsequent self-inoculation) and infectious respir ...201323888794
a sorghum xylanase inhibitor-like protein with highly potent antifungal, antitumor and hiv-1 reverse transcriptase inhibitory activities.a 25-kda protein, with an n-terminal amino acid sequence homologous to that of xylanase inhibitor and designated as xylanase inbibitor-like protein (xilp) was purified from sorghum seeds. the isolation protocol consisted of affinity chromatography, ion exchange chromatography, and gel filtration. xilp inhibited mycelial growth in various phytopathogenic fungi. the antifungal activity was thermostable and ph-stable. xilp inhibited proliferation of various cancer cell lines but did not do so in hu ...201323871041
rapid generation of human-like neutralizing monoclonal antibodies in urgent preparedness for influenza pandemics and virulent infectious diseases.the outbreaks of emerging infectious diseases caused by pathogens such as sars coronavirus, h5n1, h1n1, and recently h7n9 influenza viruses, have been associated with significant mortality and morbidity in humans. neutralizing antibodies from individuals who have recovered from an infection confer therapeutic protection to others infected with the same pathogen. however, survivors may not always be available for providing plasma or for the cloning of monoclonal antibodies (mabs).201323824680
rapid generation of human-like neutralizing monoclonal antibodies in urgent preparedness for influenza pandemics and virulent infectious diseases.the outbreaks of emerging infectious diseases caused by pathogens such as sars coronavirus, h5n1, h1n1, and recently h7n9 influenza viruses, have been associated with significant mortality and morbidity in humans. neutralizing antibodies from individuals who have recovered from an infection confer therapeutic protection to others infected with the same pathogen. however, survivors may not always be available for providing plasma or for the cloning of monoclonal antibodies (mabs).201323824680
synthesis and biological activity evaluation of 5-pyrazoline substituted 4-thiazolidinones.a series of novel 5-pyrazoline substituted 4-thiazolidinones have been synthesized. target compounds were evaluated for their anticancer activity in vitro within dtp nci protocol. among the tested compounds, the derivatives 4d and 4f were found to be the most active, which demonstrated certain sensitivity profile toward the leukemia subpanel cell lines with gi₅₀ value ranges of 2.12-4.58 μm (4d) and 1.64-3.20 μm (4f). the screening of antitrypanosomal and antiviral activities of 5-(3-naphthalen- ...201323811085
synergistic inhibitor binding to the papain-like protease of human sars coronavirus: mechanistic and inhibitor design implications.we previously developed two potent chemical classes that inhibit the essential papain-like protease (plpro) of severe acute respiratory syndrome coronavirus. in this study, we applied a novel approach to identify small fragments that act synergistically with these inhibitors. a fragment library was screened in combination with four previously developed lead inhibitors by fluorescence-based enzymatic assays. several fragment compounds synergistically enhanced the inhibitory activity of the lead i ...201323788528
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