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Disease

Influenza A causes the infectious respiratory disease Influenza, more commonly known as the Flu.^[1] Influenza has several symptoms associated with it: fever, sore throat, runny nose, headache, muscle pain, and fatigue to severe and in some cases lethal pneumonia resultant from either influenza virus or bacterial infection in the lower respiratory tract.^[2] The CDC estimated in 2019-2020 that the overall burden of Influenza was 35 million Flu-related illnesses, 16 million Flu-related medical visits, 380,000 Flu-related hospitalizations, and 20,000 Flu-related deaths [1]. The WHO estimated the global impact of annual Flu epidemics resulted in 3 to 5 million cases of severe illness, and about 290,000 to 650,000 respiratory deaths [2]. Multiple types of vaccines against Influenza currently exist: inactivated influenza vaccines (IIV4s), recombinant influenza vaccine (RIV4), and live attenuated influenza vaccine (LAIV4).^[3]

Viral RNA Classification

Influenza A virus consists of single-stranded, negative-sense RNA segments which are bound by the heterotrimeric viral RNA-dependent RNA polymerase (RDRP) and multiple copies of nucleoprotein which form the viral ribonucleoprotein (vRNP) complex.^[4]

Function of RNA Dependent RNA Polymerases

RDRPs allow viruses to replicate their genome as well as carry out transcription. RDRPs catalyze RNA-template-dependent formation of phosphodiester bonds between ribonucleotides, initiating synthesis at the 3' end of the template through a primer-dependent or independent manner proceeding in the 5' to 3' direction.^[5] RDRPs lack proofreading exonuclease activity which allows for increased rates of mutation that can be selected under pressures from the host's defense mechanisms or other environmental factors.^[6] RDRPs are a good target for antiviral drugs, as viruses depend on them to transcribe and replicate their genome so that they can infect hosts and spread. A 2020 study on the anti-Flu capabilities of 1,2,4-triazolo[1,5-a]pyrimidine-2-carboxamid-based compounds found that such compounds were able to interfere with the PA-PB1 interactions.^[7] PA and PB1 are two of the subunits which make up the heterotrimeric Influenza A RDRP that are required for the RDRP to function properly and so the compounds showed promise; however, the study called for more research into such compounds to design drugs with even better anti-Flu properties.^[8]

Structural Features^[9]

The major structure of RDRPs is formed by the fingers, palm, and thumb subdomains with an average length of the core domain being less than 500 amino acids.

Viral RNA Transcription and Translation

Conservation within Influenza A RDRP

Conclusion Section

Maybe use this to talk about why it is important to know about the RDRP structure and function, such as importance for treatments and vaccine development. (need to ask questions about this section and what specifically to include)

Possible Scenes

1) Scene that shows the nucleotide entry site

2) Scene showing conserved motifs/ residues

3) Scene showing the catalytic site (space-filling to show how things fit) (also highlight the metal ions that are present at the catalytic site)

4) Scene that colors the different subunits, such as PB1

5) Scene that shows the areas that undergo conformation changes, maybe even a scene that shows what the conformation changes are like