Polymerases of paramyxoviruses and pneumoviruses

Fearns, Rachel; Plemper, Richard K.

doi:10.1016/j.virusres.2017.01.008

Cited by 66 publications

(66 citation statements)

References 149 publications

(167 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…57 The genome of RSV is approximately 15 kilobases long and is transcribed into capped and poly-adenylated mRNAs. 58 The HMPV genome is 13 kilobases long. Current understanding of HMPV transcription is based on knowledge gained from the more extensive characterization of RSV transcription, which is the focus here.…”

Section: The Polymerase Of Rsv Hmpv and Pivsmentioning

confidence: 99%

See 1 more Smart Citation

Nucleosides for the treatment of respiratory RNA virus infections

Jordan

Stevens

Deval

2018

Antivir Chem Chemother

125

105

View full text Add to dashboard Cite

Influenza virus, respiratory syncytial virus, human metapneumovirus, parainfluenza virus, coronaviruses, and rhinoviruses are among the most common viruses causing mild seasonal colds. These RNA viruses can also cause lower respiratory tract infections leading to bronchiolitis and pneumonia. Young children, the elderly, and patients with compromised cardiac, pulmonary, or immune systems are at greatest risk for serious disease associated with these RNA virus respiratory infections. In addition, swine and avian influenza viruses, together with severe acute respiratory syndrome-associated and Middle Eastern respiratory syndrome coronaviruses, represent significant pandemic threats to the general population. In this review, we describe the current medical need resulting from respiratory infections caused by RNA viruses, which justifies drug discovery efforts to identify new therapeutic agents. The RNA polymerase of respiratory viruses represents an attractive target for nucleoside and nucleotide analogs acting as inhibitors of RNA chain synthesis. Here, we present the molecular, biochemical, and structural fundamentals of the polymerase of the four major families of RNA respiratory viruses: Orthomyxoviridae, Pneumoviridae/Paramyxoviridae, Coronaviridae, and Picornaviridae. We summarize past and current efforts to develop nucleoside and nucleotide analogs as antiviral agents against respiratory virus infections. This includes molecules with very broad antiviral spectrum such as ribavirin and T-705 (favipiravir), and others targeting more specifically one or a few virus families. Recent advances in our understanding of the structure(s) and function(s) of respiratory virus polymerases will likely support the discovery and development of novel nucleoside analogs.

show abstract

Section: The Polymerase Of Rsv Hmpv and Pivsmentioning

confidence: 99%

“…This GDP then serves as a nucleophile to attack the pRNA and results in the release of the GpppRNA. 58 The second part of the reaction consists of the MTase reaction, which uses S-adenosylmethionine to methylate nitrogen 7 and the 2 0 -oxygen of the cap.…”

Section: The Polymerase Of Rsv Hmpv and Pivsmentioning

confidence: 99%

Nucleosides for the treatment of respiratory RNA virus infections

Jordan

Stevens

Deval

2018

Antivir Chem Chemother

125

105

View full text Add to dashboard Cite

show abstract

“…Normally, when in the "replicase" mode, the viral polymerase is highly processive and skips potential stop signals within the genome. Only when it turns into a transcriptase does it recognize genomic signals such as "gene start" and "gene end" that normally begin with a cluster of Cs [34][35][36] . However, viral transcription only occurs from the leader sequence, not the trailer.…”

Section: This Is In Accordance With Previous Reports Of Infection Witmentioning

confidence: 99%

A specific sequence in the genome of respiratory syncytial virus regulates the generation of copy-back defective viral genomes

Sun

Kim

Speranza

et al. 2018

Preprint

View full text Add to dashboard Cite

Defective viral genomes of the copy-back type (cbDVGs) are the primary initiators of the antiviral immune response during infection with respiratory syncytial virus (RSV) both in vitro and in vivo. However, the mechanism governing cbDVG generation remains unknown, thereby limiting our ability to manipulate cbDVG content in order to modulate the host response to infection. Here we report a specific genomic signal that mediates the generation of RSV cbDVGs. Using a customized bioinformatics tool, we identified regions in the RSV genome frequently used to generate cbDVGs during infection. We then created a minigenome system to validate the function of one of these sequences and to determine if specific nucleotides were essential for cbDVG generation at that position. Further, we created a recombinant virus that selectively produced a specific cbDVG based on variations introduced in this sequence. The identified sequence was also found as a common site for cbDVG generation during natural RSV infections, and common cbDVGs generated at this sequence were found among samples from various infected patients. These data demonstrate that sequences encoded in the viral genome are critical determinants of the location of cbDVG generation and, therefore, this is not a stochastic process. Most importantly, these findings open the possibility of genetically manipulating cbDVG formation to modulate infection outcome.Author summaryCopy-back defective viral genomes (cbDVGs) regulate infection and pathogenesis of Mononegavirales. cbDVG are believed to arise from random errors that occur during virus replication and the predominant hypothesis is that the viral polymerase is the main driver of cbDVG generation. Here we describe a specific genomic sequence in the RSV genome that is necessary for the generation of a large proportion of the cbDVG population present during infection. We identified specific nucleotides that when modified altered cbDVG generation at this position, and we created a recombinant virus that selectively produced cbDVGs based on mutations in this sequence. These data demonstrate that the generation of RSV cbDVGs is regulated by specific viral sequences and that these sequences can be manipulated to alter the content and quality of cbDVG generated during infection.

show abstract

“…Harboring all catalytic centers of the viral polymerase complex, L has emerged as a leading drug target for many negative-sense RNA viruses because of its highly conserved nature and the density of candidate target sites including domains required for RNA synthesis, mRNA capping, or mRNA methylation [25,128,[170][171][172][173][174].…”

Section: Direct-acting Antiviralsmentioning

confidence: 99%

Status of antiviral therapeutics against rabies virus and related emerging lyssaviruses

Pont

Plemper

Schnell

2019

Current Opinion in Virology

View full text Add to dashboard Cite

Rabies virus (RABV) constitutes a major social and economic burden associated with 60,000 deaths annually worldwide. Although pre-and post-exposure treatment options are available, they are efficacious only when initiated prior to the onset of clinical symptoms. Aggravating the problem, the current RABV vaccine does not cross-protect against the emerging zoonotic phylogroup II lyssaviruses. A requirement for an uninterrupted cold chain and high cost of the immunoglobulin component of rabies prophylaxis generate an unmet need for the development of RABV-specific antivirals. We discuss desirable anti-RABV drug profiles, past efforts to address the problem and inhibitor candidates identified, and examine how the rapidly expanding structural insight into RABV protein organization has illuminated novel druggable target candidates and paved the way to structure-aided drug optimization. Special emphasis is given to the viral RNAdependent RNA polymerase complex as a promising target for direct-acting broad-spectrum RABV inhibitors.

show abstract

Polymerases of paramyxoviruses and pneumoviruses

Cited by 66 publications

References 149 publications

Nucleosides for the treatment of respiratory RNA virus infections

Nucleosides for the treatment of respiratory RNA virus infections

A specific sequence in the genome of respiratory syncytial virus regulates the generation of copy-back defective viral genomes

Status of antiviral therapeutics against rabies virus and related emerging lyssaviruses

Contact Info

Product

Resources

About