Snapshots of the influenza virus transcription-replication machine in action and implications for anti-viral drug discovery

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Influenza and SARS-CoV-2 both have single-stranded RNA as their genetic material. Although they are members of very different families of RNA viruses, they each possess an evolutionary-related RNA-dependent-RNA polymerase that transcribes and replicates the viral RNA genome. Transcription is the process whereby the polymerase uses the genome as template to synthesize viral messenger RNA (mRNA), which directs the infected cell to produce viral proteins, whereas replication generates multiple, exact genome copies that are packaged into progeny virions. Because the polymerase is essential for the replicative cycle of the virus, it is a target of choice for antiviral drugs.

Influenza RNA-dependent-RNA polymerase, which is a large, flexible complex of three distinct protein chains, transcribes the viral genome using unique mechanisms. Using state-of-the-art X-ray crystallography and electron cryo-microscopy we have obtained atomic resolution snapshots of influenza polymerase in action during the initiation, elongation and termination steps of the mRNA synthesis cycle, enabling the complete mechanism of transcription to be elucidated. Our work has underpinned the development by others of various small molecule inhibitors that target different binding sites on the influenza polymerase, one of which has recently been approved for clinical use in some countries. I will discuss whether newly developed anti-influenza drugs targeting the polymerase could also be useful against other RNA viruses, including SARS-CoV-2.

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