Flu structure heads to market

Each year hundreds of thousands of people die from seasonal outbreaks of influenza, and every so often a global flu pandemic takes the lives of many more. There is no vaccine that is 100% effective, nor a cure. But antiviral drugs can help reduce symptoms and minimize the spread of flu.

The ESRF played a vital role in elucidating the structure of targets in the virus replication machinery, namely the “cap-snatching” process. Here, a viral enzyme called polymerase cleaves off a small chemical structure called a cap from the host cell’s protein coding RNA (mRNA), causing its protein-synthesis machinery to preferentially make viral proteins.

In 2007 and 2008, experiments carried out by Stephen Cusack, head of the European Molecular Biology Laboratory (EMBL) in Grenoble, and colleagues at the joint EMBL-Grenoble University-CNRS Unit for virus host cell interactions (UVHCI), revealed the two sites in the polymerase structure where cap-snatching takes place (Nature 458 914; Nature Structural and Molecular Biology 15 500). This opened the door to structure based anti-influenza drug design, since by inhibiting the cleaving of host RNA the virus can no longer multiply. Since all influenza strains employ the cap-snatching mechanism, such inhibitors could potentially tackle a wide range of flu viruses including novel pandemic strains.

“We knew about this process for 30 years, and I’ve been working on it for 15 years, but to make progress new technologies had to be invented to identify the domains responsible for cap-snatching,” says Cusack, who trained as a theoretical solid-state physicist before turning to biology. All the structures were solved at the ESRF and there have been several follow-up studies since then. Now, says Cusack, his team wants to study the complete polymerase ensemble, rather than small parts of it, to understand how the whole viral replication machinery works. “It is a real challenge to crystallize this very dynamic particle.”

3D image of the “PA” protein domain where the cleaving of human genetic code by the flu virus takes place. The hollow canyon in the centre captures the long mRNA strand and the metal complexes at the top edges of the canyon cut off the cap. Colours denote the electrostatic surface charge. (Image credit: EMBL-UVHCI).

Spinning out

In 2009, after EMBL researchers had submitted patent applications covering the use of the two structures for drug design, Cusack co-founded Savira pharmaceuticals to develop antiviral compounds. Today he acts as an unpaid consultant to the Vienna-based firm, which employs 10 people. “I just want our research to be put to use to improve public health,” he says. “This is best achieved by both academics and industry working together as it’s really expensive and requires a lot of expertise to turn an inhibitor into a drug.”

Earlier this year Savira signed an agreement with Roche, which manufactures the antiviral influenza drug Tamiflu, to provide an exclusive license on its cap-snatching inhibitor program. In return, Savira will receive funds that could total €240 m in addition to upfront payments, research and development support and eventual royalties.

“Stephen and his team’s work at the ESRF laid the basis of Savira’s rational drug design programs,” says Savira CEO Oliver Szolar, who expects that it will take at least six to eight years before one of Savira’s flu polymerase inhibitors reaches market, following extensive toxicology studies and clinical trials. “The ESRF is still of great interest to us in this early stage,” he says. “Future structural information will still impact our development, but soon the program will move into the clinical phase.”

Matthew Chalmers

Pic caption 1: 3D image of the “PA” protein domain where the cleaving of human genetic code by the flu virus takes place. The hollow canyon in the centre captures the long mRNA strand and the metal complexes at the top edges of the canyon cut off the cap. Colours denote the electrostatic surface charge. (Image credit: EMBL-UVHCI).

This article originally appeared in ESRFnews, December 2012. 

To register for a free subscription and to rapidly receive the current issue, please go to:
http://www.esrf.fr/UsersAndScience/Publications/Newsletter/esrfnewsdigital

Top image: Key domain of flu virus polymerase with active site shown in red (Image credit: S Cusack/EMBL).