Nucleosides for the treatment of respiratory RNA virus infections

Jordan, Paul C; Stevens, Sarah K; Deval, Jerome

At the beginning and end of each viral gene lies a conserved region (CR) of 9-10 nucleotides and 12-13 nucleotides, respectively. These are termed the gene start (gs) and gene end (ge) signals with an intergenic, non-transcribed region between these genes. At the 3 0 side of the genome, prior to the first gene, is the leader (le) extragenic region and at the 5 0 end is the trailer (tr) extragenic region. The lengths of these extragenic regions can vary based on the virus but in RSV the le region is 44 nucleotides long. To transcribe its RNA, the polymerase initiates at the third nucleotide to transcribe a short uncapped transcript of about 25 nucleotides. 59 This RNA is released but the polymerase remains affixed to the template where it proceeds along until it encounters the gs signal for the first gene and subsequently begins RNA synthesis. These mRNAs are modified with a 5 0 methyl cap and when the ge signal is reached, a 3 0 polyadenylated tail is added, and the mRNA is released. The polymerase then scans for the next gs region. The genome is replicated starting at the leader promoter in a processive manner to yield a positive sense antigenome RNA. The 3 0 and 5 0 ends of the antigenome contain the trailer and leader complement. The trailer complement ultimately directs genome RNA synthesis.