The Experts below are selected from a list of 1413 Experts worldwide ranked by ideXlab platform
Tommy R. Tong - One of the best experts on this subject based on the ideXlab platform.
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Drug targets in severe acute respiratory syndrome (SARS) virus and other coronavirus infections.
Infectious disorders drug targets, 2009Co-Authors: Tommy R. TongAbstract:Coronaviruses are important human and animal pathogens of the order Nidovirales. Several new members were discovered following the emergence of SARS-CoV in human populations, including two human coronaviruses and several animal coronaviruses. They cause respiratory and gastrointestinal illnesses and have been found in the brains of patients with multiple sclerosis. The high mortality of SARS, the identification of a natural reservoir, and the well-founded fear of provoking antibody-enhanced disease as a result of vaccination fueled the ongoing efforts in anti-coronavirus drug discovery. This review presents the results of current research.
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Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV).
Perspectives in medical virology, 2006Co-Authors: Tommy R. TongAbstract:Severe acute respiratory syndrome (SARS) is caused by a coronavirus (CoV), SARSCoV. SARS-CoV belongs to the family Coronaviridae, which are enveloped RNA viruses in the order Nidovirales. Global research efforts are continuing to increase the understanding of the virus, the pathogenesis of the disease it causes (SARS), and the "heterogeneity of individual infectiousness" as well as shedding light on how to prepare for other emerging viral diseases. Promising drugs and vaccines have been identified. The milestones achieved have resulted from a truly international effort. Molecular studies dissected the adaptation of this virus as it jumped from an intermediary animal, the civet, to humans, thus providing valuable insights into processes of molecular emergence.
Jiří Červeň - One of the best experts on this subject based on the ideXlab platform.
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SARS-CoV-2 hot-spot mutations are significantly enriched within inverted repeats and CpG island loci.
Briefings in bioinformatics, 2020Co-Authors: Pratik Goswami, Martin Bartas, Natália Bohálová, Adriana Volná, Jiří Červeň, Matej Lexa, Veronika Červeňová, Petr Pečinka, Vladimír Špunda, Miroslav FojtaAbstract:SARS-CoV-2 is an intensively investigated virus from the order Nidovirales (Coronaviridae family) that causes COVID-19 disease in humans. Through enormous scientific effort, thousands of viral strains have been sequenced to date, thereby creating a strong background for deep bioinformatics studies of the SARS-CoV-2 genome. In this study, we inspected high-frequency mutations of SARS-CoV-2 and carried out systematic analyses of their overlay with inverted repeat (IR) loci and CpG islands. The main conclusion of our study is that SARS-CoV-2 hot-spot mutations are significantly enriched within both IRs and CpG island loci. This points to their role in genomic instability and may predict further mutational drive of the SARS-CoV-2 genome. Moreover, CpG islands are strongly enriched upstream from viral ORFs and thus could play important roles in transcription and the viral life cycle. We hypothesize that hypermethylation of these loci will decrease the transcription of viral ORFs and could therefore limit the progression of the disease.
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In-Depth Bioinformatic Analyses of Nidovirales Including Human SARS-CoV-2, SARS-CoV, MERS-CoV Viruses Suggest Important Roles of Non-canonical Nucleic Acid Structures in Their Lifecycles
Frontiers in microbiology, 2020Co-Authors: Martin Bartas, Václav Brázda, Natália Bohálová, Alessio Cantara, Adriana Volná, Tereza Stachurová, Kateřina Malachová, Eva B. Jagelská, Otília Porubiaková, Jiří ČerveňAbstract:Non-canonical nucleic acid structures play important roles in the regulation of molecular processes. Considering the importance of the ongoing coronavirus crisis, we decided to evaluate genomes of all coronaviruses sequenced to date (stated more broadly, the order Nidovirales) to determine if they contain non-canonical nucleic acid structures. We discovered much evidence of putative G-quadruplex sites and even much more of inverted repeats (IRs) loci, which in fact are ubiquitous along the whole genomic sequence and indicate a possible mechanism for genomic RNA packaging. The most notable enrichment of IRs was found inside 5'UTR for IRs of size 12+ nucleotides, and the most notable enrichment of putative quadruplex sites (PQSs) was located before 3'UTR, inside 5'UTR, and before mRNA. This indicates crucial regulatory roles for both IRs and PQSs. Moreover, we found multiple G-quadruplex binding motifs in human proteins having potential for binding of SARS-CoV-2 RNA. Non-canonical nucleic acids structures in Nidovirales and in novel SARS-CoV-2 are therefore promising druggable structures that can be targeted and utilized in the future.
John Ziebuhr - One of the best experts on this subject based on the ideXlab platform.
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Characterization of a bafinivirus exoribonuclease activity
Journal of General Virology, 2018Co-Authors: Izabela Durzynska, Marc Sauerwald, Nadja Karl, Ramakanth Madhugiri, John ZiebuhrAbstract:White bream virus (WBV), a poorly characterized plus-strand RNA virus infecting freshwater fish of the Cyprinidae family, is the prototype species of the genus Bafinivirus in the subfamily Torovirinae (family Coronaviridae, order Nidovirales). In common with other nidoviruses featuring >20 kilobase genomes, bafiniviruses have been predicted to encode an exoribonuclease (ExoN) in their replicase gene. Here, we used information on the substrate specificity of bafinivirus 3C-like proteases to express WBV ExoN in an active form in Escherichia coli. The 374-residue protein displayed robust 3′-to-5′ exoribonuclease activity in the presence of Mg2+ ions and, unlike its coronavirus homologues, did not require a protein cofactor for activity. Characterization of mutant forms of ExoN provided support for predictions on putative active-site and conserved zinc-binding residues. WBV ExoN was revealed to be most active on double-stranded RNA substrates containing one or two non-paired 3′-terminal nucleotides, supporting its presumed role in increasing the fidelity of the bafinivirus RNA-dependent RNA polymerase.
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Virus Research - Antiviral activity of K22 against members of the order Nidovirales
Virus research, 2018Co-Authors: Julie C. F. Rappe, John Ziebuhr, Eric J Snijder, Adriaan H. De Wilde, Christin Müller, Hanspeter Stalder, Philip V'kovski, Margo A. Brinton, Nicolas RuggliAbstract:Recently, a novel antiviral compound (K22) that inhibits replication of a broad range of animal and human coronaviruses was reported to interfere with viral RNA synthesis by impairing double-membrane vesicle (DMV) formation (Lundin et al., 2014). Here we assessed potential antiviral activities of K22 against a range of viruses representing two (sub)families of the order Nidovirales, the Arteriviridae (porcine reproductive and respiratory syndrome virus [PRRSV], equine arteritis virus [EAV] and simian hemorrhagic fever virus [SHFV]), and the Torovirinae (equine torovirus [EToV] and White Bream virus [WBV]). Possible effects of K22 on nidovirus replication were studied in suitable cell lines. K22 concentrations significantly decreasing infectious titres of the viruses included in this study ranged from 25 to 50 μM. Reduction of double-stranded RNA intermediates of viral replication in nidovirus-infected cells treated with K22 confirmed the anti-viral potential of K22. Collectively, the data show that K22 has antiviral activity against diverse lineages of nidoviruses, suggesting that the inhibitor targets a critical and conserved step during nidovirus replication.
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Antiviral activity of K22 against members of the order Nidovirales
Virus Research, 2018Co-Authors: Julie C. F. Rappe, John Ziebuhr, Eric J Snijder, Adriaan H. De Wilde, Christin Müller, Hanspeter Stalder, Philip V'kovski, Margo A. Brinton, Nicolas RuggliAbstract:Abstract Recently, a novel antiviral compound (K22) that inhibits replication of a broad range of animal and human coronaviruses was reported to interfere with viral RNA synthesis by impairing double-membrane vesicle (DMV) formation (Lundin et al., 2014). Here we assessed potential antiviral activities of K22 against a range of viruses representing two (sub)families of the order Nidovirales, the Arteriviridae (porcine reproductive and respiratory syndrome virus [PRRSV], equine arteritis virus [EAV] and simian hemorrhagic fever virus [SHFV]), and the Torovirinae (equine torovirus [EToV] and White Bream virus [WBV]). Possible effects of K22 on nidovirus replication were studied in suitable cell lines. K22 concentrations significantly decreasing infectious titres of the viruses included in this study ranged from 25 to 50 μM. Reduction of double-stranded RNA intermediates of viral replication in nidovirus-infected cells treated with K22 confirmed the anti-viral potential of K22. Collectively, the data show that K22 has antiviral activity against diverse lineages of nidoviruses, suggesting that the inhibitor targets a critical and conserved step during nidovirus replication.
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An Insect Nidovirus Emerging from a Primary Tropical Rainforest
Mbio, 2011Co-Authors: Florian Zirkel, John Ziebuhr, Andreas Kurth, Phenix Lan Quan, Thomas Briese, Heinz Ellerbrok, Georg Pauli, Fabian H. Leendertz, W. Ian Lipkin, Christian DrostenAbstract:ABSTRACT Tropical rainforests show the highest level of terrestrial biodiversity and may be an important contributor to microbial diversity. Exploitation of these ecosystems may foster the emergence of novel pathogens. We report the discovery of the first insect-associated nidovirus, tentatively named Cavally virus (CAVV). CAVV was found with a prevalence of 9.3% during a survey of mosquito-associated viruses along an anthropogenic disturbance gradient in Cote d’Ivoire. Analysis of habitat-specific virus diversity and ancestral state reconstruction demonstrated an origin of CAVV in a pristine rainforest with subsequent spread into agriculture and human settlements. Virus extension from the forest was associated with a decrease in virus diversity ( P P Nidovirales , including the families Coronavirinae and Torovirinae , but also with families in a basal phylogenetic relationship, including the families Roniviridae and Arteriviridae . Genetic markers uniquely conserved in nidoviruses, such as an endoribonuclease- and helicase-associated zinc-binding domain, are conserved in CAVV. ORF2a and -2b are predicted to code for structural proteins S and N, respectively, while ORF3a and -3b encode proteins with membrane-spanning regions. CAVV produces three subgenomic mRNAs with 5′ leader sequences (of different lengths) derived from the 5′ end of the genome. This novel cluster of mosquito-associated nidoviruses is likely to represent a novel family within the order Nidovirales . IMPORTANCE Knowledge of microbial diversity in tropical rainforests is sparse, and factors driving the emergence of novel pathogens are poorly understood. We discovered and mapped the spread and genetic evolution of a novel mosquito nidovirus from a pristine rainforest to human settlements. Notably, virus diversity decreased and prevalence increased during the process of spreading into disturbed habitats. The novel virus, tentatively termed Cavally virus, contains genetic features common to members of the order Nidovirales (families Coronaviridae , Arteriviridae , and Roniviridae ), including conservation of the replicase machinery and expression of subgenomic RNA messages, has a basal phylogenetic relationship to the family Coronaviridae , and clearly differs from the established nidovirus families. Inclusion of this putative novel family in the nidovirus phylogeny suggests that nidoviruses may have evolved from arthropods.
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characterization of bafinivirus main protease autoprocessing activities
Journal of Virology, 2011Co-Authors: Rachel Ulferts, John Ziebuhr, Thomas C MettenleiterAbstract:The production of functional nidovirus replication-transcription complexes involves extensive proteolytic processing by virus-encoded proteases. In this study, we characterized the viral main protease (Mpro) of the type species, White bream virus (WBV), of the newly established genus Bafinivirus (order Nidovirales, family Coronaviridae, subfamily Torovirinae). Comparative sequence analysis and mutagenesis data confirmed that the WBV Mpro is a picornavirus 3C-like serine protease that uses a Ser-His-Asp catalytic triad embedded in a predicted two-β-barrel fold, which is extended by a third domain at its C terminus. Bacterially expressed WBV Mpro autocatalytically released itself from flanking sequences and was able to mediate proteolytic processing in trans. Using N-terminal sequencing of autoproteolytic processing products we tentatively identified Gln↓(Ala, Thr) as a substrate consensus sequence. Mutagenesis data provided evidence to suggest that two conserved His and Thr residues are part of the S1 subsite of the enzyme's substrate-binding pocket. Interestingly, we observed two N-proximal and two C-proximal autoprocessing sites in the bacterial expression system. The detection of two major forms of Mpro, resulting from processing at two different N-proximal and one C-proximal site, in WBV-infected epithelioma papulosum cyprini cells confirmed the biological relevance of the biochemical data obtained in heterologous expression systems. To our knowledge, the use of alternative Mpro autoprocessing sites has not been described previously for other nidovirus Mpro domains. The data presented in this study lend further support to our previous conclusion that bafiniviruses represent a distinct group of viruses that significantly diverged from other phylogenetic clusters of the order Nidovirales.
Martin Bartas - One of the best experts on this subject based on the ideXlab platform.
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SARS-CoV-2 hot-spot mutations are significantly enriched within inverted repeats and CpG island loci.
Briefings in bioinformatics, 2020Co-Authors: Pratik Goswami, Martin Bartas, Natália Bohálová, Adriana Volná, Jiří Červeň, Matej Lexa, Veronika Červeňová, Petr Pečinka, Vladimír Špunda, Miroslav FojtaAbstract:SARS-CoV-2 is an intensively investigated virus from the order Nidovirales (Coronaviridae family) that causes COVID-19 disease in humans. Through enormous scientific effort, thousands of viral strains have been sequenced to date, thereby creating a strong background for deep bioinformatics studies of the SARS-CoV-2 genome. In this study, we inspected high-frequency mutations of SARS-CoV-2 and carried out systematic analyses of their overlay with inverted repeat (IR) loci and CpG islands. The main conclusion of our study is that SARS-CoV-2 hot-spot mutations are significantly enriched within both IRs and CpG island loci. This points to their role in genomic instability and may predict further mutational drive of the SARS-CoV-2 genome. Moreover, CpG islands are strongly enriched upstream from viral ORFs and thus could play important roles in transcription and the viral life cycle. We hypothesize that hypermethylation of these loci will decrease the transcription of viral ORFs and could therefore limit the progression of the disease.
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In-Depth Bioinformatic Analyses of Nidovirales Including Human SARS-CoV-2, SARS-CoV, MERS-CoV Viruses Suggest Important Roles of Non-canonical Nucleic Acid Structures in Their Lifecycles
Frontiers in microbiology, 2020Co-Authors: Martin Bartas, Václav Brázda, Natália Bohálová, Alessio Cantara, Adriana Volná, Tereza Stachurová, Kateřina Malachová, Eva B. Jagelská, Otília Porubiaková, Jiří ČerveňAbstract:Non-canonical nucleic acid structures play important roles in the regulation of molecular processes. Considering the importance of the ongoing coronavirus crisis, we decided to evaluate genomes of all coronaviruses sequenced to date (stated more broadly, the order Nidovirales) to determine if they contain non-canonical nucleic acid structures. We discovered much evidence of putative G-quadruplex sites and even much more of inverted repeats (IRs) loci, which in fact are ubiquitous along the whole genomic sequence and indicate a possible mechanism for genomic RNA packaging. The most notable enrichment of IRs was found inside 5'UTR for IRs of size 12+ nucleotides, and the most notable enrichment of putative quadruplex sites (PQSs) was located before 3'UTR, inside 5'UTR, and before mRNA. This indicates crucial regulatory roles for both IRs and PQSs. Moreover, we found multiple G-quadruplex binding motifs in human proteins having potential for binding of SARS-CoV-2 RNA. Non-canonical nucleic acids structures in Nidovirales and in novel SARS-CoV-2 are therefore promising druggable structures that can be targeted and utilized in the future.
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In-depth Bioinformatic Analyses of Human SARS-CoV-2, SARS-CoV, MERS-CoV, and Other Nidovirales Suggest Important Roles of Noncanonical Nucleic Acid Structures in Their Lifecycles
2020Co-Authors: Martin Bartas, Václav Brázda, Natália Bohálová, Alessio Cantara, Adriana Volná, Tereza Stachurová, Kateřina Malachová, Eva B. Jagelská, Otília Porubiaková, Jiri CervenAbstract:AbstractNoncanonical nucleic acid structures play important roles in the regulation of molecular processes. Considering the importance of the ongoing coronavirus crisis, we decided to evaluate genomes of all coronaviruses sequenced to date (stated more broadly, the order Nidovirales) to determine if they contain noncanonical nucleic acid structures. We discovered much evidence of putative G-quadruplex sites and even much more of inverted repeats (IRs) loci, which in fact are ubiquitous along the whole genomic sequence and indicate a possible mechanism for genomic RNA packaging. The most notable enrichment of IRs was found inside 5′UTR for IRs of size 12+ nucleotides, and the most notable enrichment of putative quadruplex sites (PQSs) was located before 3′UTR, inside 5′UTR, and before mRNA. This indicates crucial regulatory roles for both IRs and PQSs. Moreover, we found multiple G-quadruplex binding motifs in human proteins having potential for binding of SARS-CoV-2 RNA. Noncanonical nucleic acids structures in Nidovirales and in novel SARS-CoV-2 are therefore promising druggable structures that can be targeted and utilized in the future.
Qi Cheng - One of the best experts on this subject based on the ideXlab platform.
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Product of natural evolution (SARS, MERS, and SARS-CoV-2); deadly diseases, from SARS to SARS-CoV-2.
Human Vaccines & Immunotherapeutics, 2020Co-Authors: Mohamad Hesam Shahrajabian, Wenli Sun, Qi ChengAbstract:SARS-CoV-2, the virus causing COVID-19, is a single-stranded RNA virus belonging to the order Nidovirales, family Coronaviridae, and subfamily Coronavirinae. SARS-CoV-2 entry to cellsis initiated by the binding of the viral spike protein (S) to its cellular receptor. The roles of S protein in receptor binding and membrane fusion makes it a prominent target for vaccine development. SARS-CoV-2 genome sequence analysis has shown that this virus belongs to the beta-coronavirus genus, which includes Bat SARS-like coronavirus, SARS-CoV and MERS-CoV. A vaccine should induce a balanced immune response to elicit protective immunity. In this review, we compare and contrast these three important CoV diseases and how they inform on vaccine development.