Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Catching the cap-snatcher

03.08.2012
Structural analysis opens the way to new anti-influenza drugs

Researchers at the European Molecular Biology Laboratory (EMBL) in Grenoble, France, have determined the detailed 3-dimensional structure of part of the flu virus’ RNA polymerase, an enzyme that is crucial for influenza virus replication. This important finding is published today in PLoS Pathogens.

The research was done on the 2009 pandemic influenza strain but it will help scientists to design innovative drugs against all the different influenza strains, and potentially lead to a new class of anti-flu drugs in the next 5-10 years.

The scientists focused on the endonuclease part of the viral RNA polymerase. The endonuclease is responsible for a unique mechanism called ‘cap-snatching’ that allows the virus to trick its host cell into producing viral proteins. In human cells the translation of messenger RNA (mRNA) strands into proteins requires a special structure, called the “cap”, at the beginning of each mRNA.

When the influenza virus infects a host cell its endonuclease “snatches” that cap from the cell’s own mRNA. Another part of its RNA polymerase then uses it as the starting point for synthesizing viral mRNA. With the correct cap structure at the beginning, viral mRNA can then hijack the protein-production machinery of the infected cell to make viral proteins, which assemble into new viruses that will spread the infection.

The team led by Stephen Cusack, Head of EMBL Grenoble, analyzed crystals of endonuclease from the 2009 pandemic influenza strain using the high intensity X-ray beams at the European Synchrotron Radiation Facility (ESRF). The researchers were able to determine the 3D atomic structure of the enzyme and to visualize how several different small molecule inhibitors bind to and block its active site. If the active site of the endonuclease is blocked by an inhibitor the enzyme cannot bind its normal substrate, the host cell mRNA, and viral replication is prevented.

The active site of the endonuclease is shaped like a cave with two metal ions at the bottom. Cusack and colleagues found that all the inhibitors they studied bind to those two metal ions but, depending on their shapes, different inhibitors bind differently to the amino-acids of the cave’s walls.

“Based on this detailed structural information we can now design new synthetic chemicals which bind even more tightly to the endonuclease active site and thus will potentially be more potent inhibitors of influenza virus replication,” explains Stephen Cusack. “We can even try to build in anti-drug resistance by making sure the inhibitors only contact those amino acids that the virus cannot mutate since they are essential for the normal activity of the polymerase.”

Because the cap-snatching mechanism is common to all influenza strains, new potent endonuclease inhibitors should be effective against seasonal flu, novel pandemic strains or highly pathogenic H5N1 bird flu. EMBL scientists are working with EMBL’s spin-off company Savira pharmaceuticals, in partnership with Roche, to further develop influenza inhibitors. Promising candidates will be tested first for efficacy in cell culture, ultimately moving into clinical trials on humans.

This research was partly funded by the European commission, through the FP7 research grant awarded to the FluPharm project.

Policy regarding use
EMBL press and picture releases including photographs, graphics and videos are copyrighted by EMBL. They may be freely reprinted and distributed for non-commercial use via print, broadcast and electronic media, provided that proper attribution to authors, photographers and designers is made.
CONTACTS
Sonia Furtado Neves
EMBL Press Officer
Meyerhofstr. 1, 69117 Heidelberg, Germany
Tel.: +49 (0)6221 387 8263
Fax: +49 (0)6221 387 8525
sonia.furtado@embl.de
www.embl.org
Keep up-to-date with EMBL Research News at: www.embl.org/news
Isabelle Kling
Project Officer – CommHERE
European Molecular Biology Laboratory - EMBL
Meyerhofstr. 1
69117 Heidelberg
Germany
T: +49 6221 387 8355
isabelle.kling@embl.de
www.embl.org
www.commhere.eu/

Isabelle Kling | EMBL Research News
Further information:
http://www.embl.org
http://dx.plos.org/10.1371/journal.ppat.1002831
http://www.embl.org/press/2012/120802_Grenoble

More articles from Life Sciences:

nachricht Multi-institutional collaboration uncovers how molecular machines assemble
02.12.2016 | Salk Institute

nachricht Fertilized egg cells trigger and monitor loss of sperm’s epigenetic memory
02.12.2016 | IMBA - Institut für Molekulare Biotechnologie der Österreichischen Akademie der Wissenschaften GmbH

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Novel silicon etching technique crafts 3-D gradient refractive index micro-optics

A multi-institutional research collaboration has created a novel approach for fabricating three-dimensional micro-optics through the shape-defined formation of porous silicon (PSi), with broad impacts in integrated optoelectronics, imaging, and photovoltaics.

Working with colleagues at Stanford and The Dow Chemical Company, researchers at the University of Illinois at Urbana-Champaign fabricated 3-D birefringent...

Im Focus: Quantum Particles Form Droplets

In experiments with magnetic atoms conducted at extremely low temperatures, scientists have demonstrated a unique phase of matter: The atoms form a new type of quantum liquid or quantum droplet state. These so called quantum droplets may preserve their form in absence of external confinement because of quantum effects. The joint team of experimental physicists from Innsbruck and theoretical physicists from Hannover report on their findings in the journal Physical Review X.

“Our Quantum droplets are in the gas phase but they still drop like a rock,” explains experimental physicist Francesca Ferlaino when talking about the...

Im Focus: MADMAX: Max Planck Institute for Physics takes up axion research

The Max Planck Institute for Physics (MPP) is opening up a new research field. A workshop from November 21 - 22, 2016 will mark the start of activities for an innovative axion experiment. Axions are still only purely hypothetical particles. Their detection could solve two fundamental problems in particle physics: What dark matter consists of and why it has not yet been possible to directly observe a CP violation for the strong interaction.

The “MADMAX” project is the MPP’s commitment to axion research. Axions are so far only a theoretical prediction and are difficult to detect: on the one hand,...

Im Focus: Molecules change shape when wet

Broadband rotational spectroscopy unravels structural reshaping of isolated molecules in the gas phase to accommodate water

In two recent publications in the Journal of Chemical Physics and in the Journal of Physical Chemistry Letters, researchers around Melanie Schnell from the Max...

Im Focus: Fraunhofer ISE Develops Highly Compact, High Frequency DC/DC Converter for Aviation

The efficiency of power electronic systems is not solely dependent on electrical efficiency but also on weight, for example, in mobile systems. When the weight of relevant components and devices in airplanes, for instance, is reduced, fuel savings can be achieved and correspondingly greenhouse gas emissions decreased. New materials and components based on gallium nitride (GaN) can help to reduce weight and increase the efficiency. With these new materials, power electronic switches can be operated at higher switching frequency, resulting in higher power density and lower material costs.

Researchers at the Fraunhofer Institute for Solar Energy Systems ISE together with partners have investigated how these materials can be used to make power...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

ICTM Conference 2017: Production technology for turbomachine manufacturing of the future

16.11.2016 | Event News

Innovation Day Laser Technology – Laser Additive Manufacturing

01.11.2016 | Event News

#IC2S2: When Social Science meets Computer Science - GESIS will host the IC2S2 conference 2017

14.10.2016 | Event News

 
Latest News

UTSA study describes new minimally invasive device to treat cancer and other illnesses

02.12.2016 | Medical Engineering

Plasma-zapping process could yield trans fat-free soybean oil product

02.12.2016 | Agricultural and Forestry Science

What do Netflix, Google and planetary systems have in common?

02.12.2016 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>