Influenza polymerase (light cyan) in the process of synthesising messenger RNA (slate blue) by copying the genomic viral RNA template (yellow). IMAGE: Stephen Cusack / EMBL
“Studying and understanding the unique mechanisms of transcription and replication used by influenza virus is essential to fight its spread,” explains EMBL group leader Stephen Cusack.
A decade long study
Stephen Cusack and his research group at EMBL Grenoble started to work on influenza polymerase more than 20 years ago. In 2014, the group published the first crystal structures of the complete polymerase machine. However, attempts to structurally characterise the different states of actively transcribing influenza polymerase have so far been unsuccessful.
“All studies so far have looked at the resting structure of the polymerase machine; we’ve never observed it actually doing anything,” says Tomas Kouba, a postdoc in the group who carried out much of the work.
Target point for new drugs
Despite its familiarity, the influenza virus – some strains of which are among the top ten most dangerous viruses in the world – is far from being well understood. Up to 500,000 people worldwide die from influenza each year, according to the World Health Organization, with potentially much higher mortality rates when a new pandemic flu strain emerges. Vaccination is not always effective and anti-influenza drugs are needed as a complementary treatment option.
As the viral polymerase is essential for the replication of the flu virus, it is a prime target for the development of new anti-influenza drugs. As such, the results gained by the EMBL group give new insights to help design the next generation of anti-influenza drugs. The advantage of drugs that stop the polymerase functioning is that it is much less likely that the virus will mutate in a way that would render the drug useless.
“Our results contribute the first snapshots of a movie that will show the complete transcription cycle of influenza polymerase from initiation to termination,” explains Cusack. The group will continue to use the powerful technique of cryo-electron microscopy to fill in the missing steps.
Source article
Kouba, T, Drncová, P, and Cusack, S. Structural snapshots of actively transcribing influenza polymerase. Nature Structural & Molecular Biology, published online 3 June 2019. DOI: 10.1038/s41594-019-0232-z
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