Cap snatching

Most viruses snatch 15-20 nucleotides except for the families Arenaviridae and Nairoviridae and the genus Thogotovirus (Orthomyxoviridae) which use a shorter strand.

[4] Cap-snatching occurs in three general steps: 1) The viral RdRp or N protein binds to the host mRNA 5’-methylated cap-1 or cap-2 structure.

The PA subunit subsequently cleaves the sequence 10-13 nucleotides from the cap structure via endonuclease activity at the N terminus.

[5] The exact cleavage location is dependent both on the distance between the PB2 and the PA of the RdRp (around 50 angstroms or 10-13 nucleotides) and also the sequence of the mRNA.

The vRNA 3’-UCGUUUU nucleotides are not bound to the polymerase but rather are free for complementary binding with the capped RNA primer to confer stability.

[6] Finally, the PB1 subunit completes chain elongation in the canonical 5’ to 3’ direction, releasing the cap, but keeping the 5’ end bound.

The viral 3’ poly-A tail is added at the end of transcription by polymerase stuttering from the steric hindrance of the vRNA loop.

Additionally, by reducing Pol II abundance, influenza can begin to shut off critical host transcription.

PA is a member of the PD(D/E)XK nuclease family, which uses divalent metal ions to cleave nucleic acid.

[10] The drug utilizes knowledge about cap snatching by targeting and inhibiting the endonuclease function of the PA subunit, which will prevent the virus from initiating transcription.

The two-domain model has also been prosed for hantaviruses, but the N protein in the rift valley fever virus (Phenuiviridae) does not possess the same features.