The Eukaryotic Elongation Factor 1A Is Critical for Genome Replication of the Paramyxovirus Respiratory Syncytial Virus

Wei, Ting; Li, Dongsheng; Marcial, Daneth L.; Khan, Moshin; Lin, Min-Hsuan; Snape, Natale; Ghildyal, Reena; Harrich, David; Spann, Kirsten

doi:10.1371/journal.pone.0114447

Cited by 27 publications

(34 citation statements)

References 34 publications

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“…It may be possible to overcome this restriction by targeting a host cell-derived cofactor of the complex that is likewise indispensible for RdRp activity. For instance, the human translation elongation factor eEF1A is known to be required for VSV RdRp transcriptase activity ( Das et al, 1998 ; Qanungo et al, 2004 ) and was recently shown to be critically involved also in RSV replication ( Wei et al, 2014 ). A general requirement of eEF1A and/or additional host factors for paramyxovirus RdRp activity is possible, but direct therapeutic targeting of, for instance, eEF1A will likely be prohibited by its central role in host protein synthesis.…”

Section: Development Of Antiviral Therapeuticsmentioning

confidence: 99%

The paramyxovirus polymerase complex as a target for next-generation anti-paramyxovirus therapeutics

Cox

Plemper

2015

Front. Microbiol.

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The paramyxovirus family includes major human and animal pathogens, including measles virus, mumps virus, and human respiratory syncytial virus (RSV), as well as the emerging zoonotic Hendra and Nipah viruses. In the U.S., RSV is the leading cause of infant hospitalizations due to viral infectious disease. Despite their clinical significance, effective drugs for the improved management of paramyxovirus disease are lacking. The development of novel anti-paramyxovirus therapeutics is therefore urgently needed. Paramyxoviruses contain RNA genomes of negative polarity, necessitating a virus-encoded RNA-dependent RNA polymerase (RdRp) complex for replication and transcription. Since an equivalent enzymatic activity is absent in host cells, the RdRp complex represents an attractive druggable target, although structure-guided drug development campaigns are hampered by the lack of high-resolution RdRp crystal structures. Here, we review the current structural and functional insight into the paramyxovirus polymerase complex in conjunction with an evaluation of the mechanism of activity and developmental status of available experimental RdRp inhibitors. Our assessment spotlights the importance of the RdRp complex as a premier target for therapeutic intervention and examines how high-resolution insight into the organization of the complex will pave the path toward the structure-guided design and optimization of much-needed next-generation paramyxovirus RdRp blockers.

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Section: Development Of Antiviral Therapeuticsmentioning

confidence: 99%

The paramyxovirus polymerase complex as a target for next-generation anti-paramyxovirus therapeutics

Cox

Plemper

2015

Front. Microbiol.

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“…In fact, EF1α assists replication of many RNA viruses, such as the respiratory syncytialvirus (RSV). In this case, down-regulation of EF1α restricts the expression of viral genomic RNA and the release of infectious virus (Wei, et al 2014); in parasites, EF1α has also been implicated in pathogenesis (Nandan and Reiner 2005) and host cell invasion (Matsubayashi, et al 2013).…”

Section: Implications For Infection Biologymentioning

confidence: 99%

Protein network analysis indicates that Ebola virus, Neisseria meningitidis and Trypanosoma brucei trigger common host defense response pathways

Gupta

Ponte-Sucre

Bencúrová

et al. 2019

Preprint

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Background: Sepsis is the most severe final state of infection. Might pathogens belonging to different kingdoms of life and pathogen classes trigger analogous responses pathways in the host? Is there a common denominator or strategy to prevent it? Here we use interactomics and comparative evolutionary analysis of three serious infectious pathogens, spanning viruses, bacteria and parasites: Filovirus ebolavirus (ZE; Zaire ebolavirus , Bundibugyo ebolavirus), Neisseria meningitides (NM), and Trypanosoma brucei (Tb) that target the blood during their infectious life cycle. Results: We analyze 2797 unique human proteins targeted by the pathogens. The comparison resulted in specific and shared protein-protein interactions (PPIs) with each pathogen, derived from orthology searches of experimentally validated PPIs. Furthermore, we narrow down the data set of effected genes of the human (defense) immune response and describe human proteins predicted to participate in at least two of the compared host-pathogen networks. Only four proteins were common to all three host-pathogen interactomes. This interaction clade of four proteins, common to all three host-pathogen networks, suggests a central cluster of host response formed by elongation factor 1-alpha 1 (EF-1-alpha-1), the SWI/SNF complex subunit SMARCC2 (matrix-associated actin-dependent regulator of chromatin subfamily C), the dolichyl-diphosphooligosaccharide--protein glycosyltransferase subunit 1, and the tubulin beta-5 chain. These hub proteins are functionally connected, suggesting according to the collected data including experimental information on VP24 from Ebola virus that these, as well as some joined interaction partners, may orchestrate a common host response to infection.

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“…Multiple catalytic centers present in the L protein and a number of essential protein-protein interactions between viral proteins such as L and P and P-L and the encapsidated RNP template and viral polymerase components and mandatory host co-factors such as the human translation elongation factor eEF1A (108) provide a multitude of candidate druggable targets for small-molecule inhibition. A frequent problem especially of allosteric polymerase blockers is a narrow indication spectrum, however, restricting potent antiviral activity to a specific family member or pathogens of a single genus within the family (109, 110).…”

Section: Antiviral Strategies Targeting Pneumo- and Paramyxovirus Polmentioning

confidence: 99%

Polymerases of paramyxoviruses and pneumoviruses

Fearns

Plemper

2017

Virus Research

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The paramyxo- and pneumoviruses are members of the order Mononegavirales, a group of viruses with non-segmented, negative strand RNA genomes. The polymerases of these viruses are multi-functional complexes, capable of transcribing subgenomic capped and polyadenylated mRNAs and replicating the genome. Although there is no native structure available for any complete paramyxo- or pneumovirus polymerase, functional and structural studies of a fragment of a pneumovirus polymerase protein and mutation analyses and resistance profiling of small-molecule inhibitors have generated a wealth of mechanistic information. This review integrates these data with the structure of a related polymerase, identifying similarities, differences, gaps in knowledge, and avenues for antiviral drug development.

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The Eukaryotic Elongation Factor 1A Is Critical for Genome Replication of the Paramyxovirus Respiratory Syncytial Virus

Cited by 27 publications

References 34 publications

The paramyxovirus polymerase complex as a target for next-generation anti-paramyxovirus therapeutics

The paramyxovirus polymerase complex as a target for next-generation anti-paramyxovirus therapeutics

Protein network analysis indicates that Ebola virus, Neisseria meningitidis and Trypanosoma brucei trigger common host defense response pathways

Polymerases of paramyxoviruses and pneumoviruses

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