The future of antivirals

Debing, Yannick; Neyts, Johan; Delang, Leen

doi:10.1097/qco.0000000000000212

Cited by 58 publications

(34 citation statements)

References 74 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…As a proof of principle, we screened a set of compounds targeting RNA synthesis and found that cPol and vPol are differently inhibited by the 2΄F-2΄dNTP nucleoside analogues. This result could be exploited to develop novel influenza polymerase inhibitors (57). …”

Section: Discussionmentioning

confidence: 99%

Anin vitrofluorescence based study of initiation of RNA synthesis by influenza B polymerase

2017

View full text Add to dashboard Cite

Influenza polymerase replicates, via a complementary RNA intermediate (cRNA), and transcribes the eight viral RNA (vRNA) genome segments. To initiate RNA synthesis it is bound to the conserved 5΄ and 3΄ extremities of the vRNA or cRNA (the ‘promoter’). 5΄-3΄ base-pairing in the distal promoter region is essential to position the template RNA at the polymerase active site, as shown by a new crystal structure with the 3΄ end threading through the template entry tunnel. We develop fluorescence polarization assays to quantify initiation of cap-primed (transcription) or unprimed (replication) RNA synthesis by recombinant influenza B polymerase bound to the vRNA or cRNA promoter. The rate-limiting step is formation of a primed initiation complex with minimally ApG required to stabilize the 3΄ end of the template within the active-site. Polymerase bound to the vRNA promoter initiates RNA synthesis terminally, while the cRNA promoter directs internal initiation at a significantly lower rate. Progression to elongation requires breaking the promoter 5΄-3΄ base-pairing region and favourable compensation by the emerging template-product base-pairs. The RNA synthesis assay is adaptable to high-throughput screening for polymerase inhibitors. In a pilot study, we find that initiation at the cRNA promoter is unusually susceptible to inhibition by 2΄F-2΄dNTPs.

show abstract

Section: Discussionmentioning

confidence: 99%

Anin vitrofluorescence based study of initiation of RNA synthesis by influenza B polymerase

2017

View full text Add to dashboard Cite

show abstract

“…Other powerful methods to be used in combination with glycomics and proteomics include RNA interference, CRISPR/Cas9 knockout, genome-wide haploid screens, cell-based arrays, drug-based approaches, and utilization of the microarray-characterized set of cells provided by US National Cancer Institute. We refer the reader elsewhere for further information on these methods [160][161][162][163][164][165][166]. A clear advantage of labelfree glycomics and proteomics technologies is, however, the minimal system perturbation in particular when untagged endogenous bait glycans and proteins are used.…”

Section: Alternative Approaches For Receptor Discoverymentioning

confidence: 99%

Glycomics and Proteomics Approaches to Investigate Early Adenovirus–Host Cell Interactions

Laßwitz

Chandra

Arnberg

2018

Journal of Molecular Biology

View full text Add to dashboard Cite

Adenoviruses as most viruses rely on glycan and protein interactions to attach to and enter susceptible host cells. The Adenoviridae family comprises more than 80 human types and they differ in their attachment factor and receptor usage, which likely contributes to the diverse tropism of the different types. In the past years, methods to systematically identify glycan and protein interactions have advanced. In particular sensitivity, speed and coverage of mass spectrometric analyses allow for high-throughput identification of glycans and peptides separated by liquid chromatography. Also, developments in glycan microarray technologies have led to targeted, high-throughput screening and identification of glycan-based receptors. The mapping of cell surface interactions of the diverse adenovirus types has implications for cell, tissue, and species tropism as well as drug development. Here we review known adenovirus interactions with glycan- and protein-based receptors, as well as glycomics and proteomics strategies to identify yet elusive virus receptors and attachment factors. We finally discuss challenges, bottlenecks, and future research directions in the field of non-enveloped virus entry into host cells.

show abstract

“…However, a broad catalogue of antivirals is required to make this strategy feasible, and this is only available for a small number of viruses such as HIV. Although some drugs can inhibit multiple viruses (e.g., nucleoside analogues with activity against both HIV and HBV [Debing, Neyts, & Delang, 2015;Mendes-Correa & Nunez, 2010]), viral enzyme-targeting drugs usually fail at protecting even against closely related virus species. By contrast, inhibition of cellular factors required for virus infection is expected to provide a higher barrier to the emergence of resistance.…”

mentioning

confidence: 99%

“…Because different viruses often exploit common cellular pathways, host proteins are promising targets for the development of broad-spectrum antiviral therapies (Martinez, Sasse, Bronstrup, Diez, & Meyerhans, 2015;Zhu, Meng, Wang, & Wang, 2015). Cellular kinases (Schor & Einav, 2018), cyclophilins (Dawar, Tu, Khattak, Mei, & Lin, 2017;Debing et al, 2015), and heat-shock proteins (Geller, Taguwa, & Frydman, 2012; represent potential candidates for such antiviral intervention.…”

mentioning

confidence: 99%

Unconventional RNA‐binding proteins step into the virus–host battlefront

2018

View full text Add to dashboard Cite

The crucial participation of cellular RNA-binding proteins (RBPs) in virtually all steps of virus infection has been known for decades. However, most of the studies characterizing this phenomenon have focused on well-established RBPs harboring classical RNA-binding domains (RBDs). Recent proteome-wide approaches have greatly expanded the census of RBPs, discovering hundreds of proteins that interact with RNA through unconventional RBDs. These domains include protein-protein interaction platforms, enzymatic cores, and intrinsically disordered regions. Here, we compared the experimentally determined census of RBPs to gene ontology terms and literature, finding that 472 proteins have previous links with viruses. We discuss what these proteins are and what their roles in infection might be. We also review some of the pioneering examples of unorthodox RBPs whose RNA-binding activity has been shown to be critical for virus infection. Finally, we highlight the potential of these proteins for host-based therapies against viruses. This article is categorized under: RNA Interactions with Proteins and Other Molecules > Protein-RNA Interactions: Functional Implications RNA in Disease and Development > RNA in Disease RNA Interactions with Proteins and Other Molecules > RNA-Protein Complexes.

show abstract

The future of antivirals

Abstract: Despite the recent advances, the BSAA field is still in its infancy. Nevertheless, the discovery and development of such molecules will be a key aim of antiviral research in the coming decades.

Cited by 58 publications

References 74 publications

Anin vitrofluorescence based study of initiation of RNA synthesis by influenza B polymerase

Anin vitrofluorescence based study of initiation of RNA synthesis by influenza B polymerase

Glycomics and Proteomics Approaches to Investigate Early Adenovirus–Host Cell Interactions

Unconventional RNA‐binding proteins step into the virus–host battlefront

Contact Info

Product

Resources

About