Inhibitors of Respiratory Syncytial Virus Replication Target Cotranscriptional mRNA Guanylylation by Viral RNA-Dependent RNA Polymerase

Liuzzi, Michel; Mason, Stephen W.; Cartier, Mireille; Lawetz, Carole; McCollum, Robert S.; Dansereau, Nathalie; Bolger, Gordon; Lapeyre, Nicole; Gaudette, Yvon; Lagace, Lisette; Massariol, Marie-Josée; Do, Florence; Whitehead, Paul; Lamarre, Lynne; Scouten, Erika; Bordeleau, Josée; Landry, Serge; Rancourt, Jean; Fazal, Gulrez et Simoneau, Bruno (2005). « Inhibitors of Respiratory Syncytial Virus Replication Target Cotranscriptional mRNA Guanylylation by Viral RNA-Dependent RNA Polymerase ». Journal of Virology, 79(20), pp. 13105-13115.

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Respiratory syncytial virus (RSV) is a major cause of respiratory illness in infants, immunocompromised patients, and the elderly. New antiviral agents would be important tools in the treatment of acute RSV disease. RSV encodes its own RNA-dependent RNA polymerase that is responsible for the synthesis of both genomic RNA and subgenomic mRNAs. The viral polymerase also cotranscriptionally caps and polyadenylates the RSV mRNAs at their 5' and 3' ends, respectively. We have previously reported the discovery of the first nonnucleoside transcriptase inhibitor of RSV polymerase through high-throughput screening. Here we report the design of inhibitors that have improved potency both in vitro and in antiviral assays and that also exhibit activity in a mouse model of RSV infection. We have isolated virus with reduced susceptibility to this class of inhibitors. The mutations conferring resistance mapped to a novel motif within the RSV L gene, which encodes the catalytic subunit of RSV polymerase. This motif is distinct from the catalytic region of the L protein and bears some similarity to the nucleotide binding domain within nucleoside diphosphate kinases. These findings lead to the hypothesis that this class of inhibitors may block synthesis of RSV mRNAs by inhibiting guanylylation of viral transcripts. We show that short transcripts produced in the presence of inhibitor in vitro do not contain a 5' cap but, instead, are triphosphorylated, confirming this hypothesis. These inhibitors constitute useful tools for elucidating the molecular mechanism of RSV capping and represent valid leads for the development of novel anti-RSV therapeutics.

Type: Article de revue scientifique
Mots-clés ou Sujets: 3' untranslated region; 5' untranslated region; aging; animal experiment; animal model; antiviral activity; article; controlled study; drug design; drug determination; drug potency; drug targeting; enzyme active site; female; high throughput screening; human; human cell; immune deficiency; in vitro study; messenger rna guanylylation; mouse; nonhuman; nucleotide sequence; priority journal; protein domain; protein motif; Respiratory syncytial pneumovirus; respiratory tract disease; respiratory tract infection; RNA processing; RNA transcription; virus gene; virus genome; virus inhibition; virus isolation; virus mutant
Unité d'appartenance: Faculté des sciences > Département de chimie
Déposé par: delegation Jean Rancourt
Date de dépôt: 18 mai 2016 19:47
Dernière modification: 18 mai 2016 19:47
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