Abstract
Human respiratory syncytial virus (HRSV) causes bronchiolitis and pneumonia. The role of methyltransferase (MTase) activity of HRSV polymerase in viral replication is unknown. Literature reviews of similar viral MTases and homology- modeling of RSV MTase bound to GTP and S-adenosylmethionine (SAM) have shown sequence similarity and the conserved catalytic residues (K-D-K-E) and the SAM-binding (GXGXG) domain. Combined with the recent reports of the importance of 2’O methylation of viral RNAs in the host innate immune response evasion, and its proposed role in viral replication, HRSV MTase holds promise as a potential antiviral target. Further biological validation of HRSV MTase could facilitate the discovery of novel HRSV antivirals targeting MTase enzyme activity.
Highlights
Human respiratory syncytial virus (HRSV) causes bronchiolitis and pneumonia
The purpose of our opinion article is to draw a wider attention to the unmet medical need for treating HRSV infections and to highlight MTase as a potential target
Key residues in HRSV MTase catalytic motif and SAM binding domain seem to be conserved between different subtypes A and B of HRSV, pneumoviruses and negative sense non-segmented viruses except Bornaviridae family members21,39
Summary
KU Leuven, Leuven, Any reports and responses or comments on the article can be found at the end of the article. Genetic support for HRSV MTase role in viral replication Recombinant VSVs (a prototype of nsNS RNA viruses) with point mutations in the methyltransferase catalytic site (rVSVK1651A, -D1762A, and -E1833Q) were reported to be defective in cap methylation and demonstrated reduced growth in cell culture and mice. Key residues in HRSV MTase catalytic motif and SAM binding domain seem to be conserved between different subtypes A and B of HRSV, pneumoviruses and negative sense non-segmented viruses except Bornaviridae family members21,39 Such a conserved sequence could provide a basis for structure-based design for pan-antiviral inhibitors targeting viral MTase. The high degree of sequence conservation of the HRSV MTase catalytic residues and the fundamental differences between viral and host capping mechanisms combined with the potential for the restoration of innate immune response that could degrade viral mRNAs makes HRSV MTase a logical target for HRSV drug discovery efforts.
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