Experts identify key area of bird flu virus

[AlaskaDenise]

(I don't recall seeing this posted here)
--------------------------------------------------
HONG KONG, Feb 5 (Reuters) - Two teams of researchers say they have identified a key area of the H5N1 bird flu virus which appears to be involved in its replication and hope the discovery could speed up the design of new drugs.

In separate articles published in the journal Nature, the teams from France and China said the region of the virus could be an important target for the development of new drugs.

A member of the Chinese team said they had examined three proteins in the area and found they were involved in binding the virus to human cells and in virus replication.

"It (the area) has multi-functions ... and can be used as a target for new drugs," Yingfang Liu at the Institute of Biophysics of the Chinese Academy of Sciences told Reuters.

It is feared the H5N1 virus could kill millions in a pandemic if it ever mutated to transmit efficiently among people. There are currently two drugs, Roche's (ROG.VX) Tamiflu and GlaxoSmithKline Plc's (GSK.L) Relenza, which experts hope can be used to fight H5N1.

But reports of the growing drug resistance of some H5N1 strains have led researchers to try to design new drugs.

"Influenza viruses change (mutate) very frequently and for any disease, you will need different drugs. Our work provides a platform for drug (design)," Liu said.

The French team, led by Stephen Cusack at the Unit of Virus Host-Cell Interactions in Grenoble in southeast France, said their findings would help in the development of "inhibitors", or blockers, as potential new anti-influenza drugs.

Since 2003, the virus has infected 404 people in 15 countries and killed 254 of them. It has killed or forced the destruction of more than 300 million birds as it spread to 61 countries in Asia, the Midde East, Europe and Africa. (Reporting by Tan Ee Lyn; editing by Andrew Roche)

http://www.reuters.com/article/europeCrisis/idUST115796

[AlaskaDenise]

Re: Experts identify key area of bird flu virus

New findings reveal how influenza virus hijacks human cells
Scientists provide atomic resolution details of a promising drug target in influenza virus



IMAGE: High resolution image of the key domain of the influenza virus polymerase. The active site responsible for RNA cleavage is shown in red. Its activity is crucial for the virus...

Click here for more information.



Influenza is and remains a disease to reckon with. Seasonal epidemics around the world kill several hundred thousand people every year. In the light of looming pandemics if bird flu strains develop the ability to infect humans easily, new drugs and vaccines are desperately sought. Researchers at the European Molecular Biology Laboratory (EMBL) and the joint Unit of Virus Host-Cell Interaction (UVHCI) of EMBL, the University Joseph Fourier (UJF) and the National Centre for Scientific Research (CNRS), in Grenoble, France, have now precisely defined an important drug target in influenza. In this week's Nature they publish a high-resolution image of a crucial protein domain that allows the virus to hijack human cells and multiply in them.

When the influenza virus infects a host cell its goal is to produce many copies of itself that go on to attack even more cells. A viral enzyme, called polymerase, is key to this process. It both copies the genetic material of the virus and steers the host cell machinery towards the synthesis of viral proteins. It does this by stealing a small tag, called a cap, from host cell RNA molecules and adding it onto its own. The cap is a short extra piece of RNA, which must be present at the beginning of all messenger RNAs (mRNAs) to direct the cell's protein-synthesis machinery to the starting point. The viral polymerase binds to host cell mRNA via its cap, cuts the cap off and adds it to the beginning of its own mRNA – a process known as 'cap snatching'. But exactly how the polymerase achieves this and which of the three subunits of the enzyme does what, has remained controversial.

Researchers of the groups of Rob Ruigrok at the UVHCI and Stephen Cusack at EMBL have now discovered that part of a polymerase subunit called PA is responsible for cleaving the cap off the host mRNA.

"Our results came as a big surprise, because everybody thought that the cleaving activity resides in a different part of the polymerase," explains Rob Ruigrok, Vice-Director of the UVHCI.

"These new insights make PA a promising antiviral drug target. Inhibiting the cleaving of the cap is an efficient way to stop infection, because the virus can no longer multiply. Now we know where to focus drug design efforts," adds Stephen Cusack, Head of EMBL Grenoble and Director of the UVHCI.

The researchers produced crystals of the crucial PA domain and examined them with the powerful X-ray beams of the European Synchrotron Radiation Facility (ESRF) in Grenoble. The high-resolution image of the domain reveals the individual amino acids that constitute the active site responsible for cleaving the RNA; information that could guide the design of future antiviral drugs.

Only a few months ago the same group of scientists had already identified another key part of the influenza polymerase; a domain in the subunit called PB2 that recognises and binds to the host cap. Taken together the two findings provide a close-to-complete picture of the cap snatching mechanism that allows the influenza virus to take control over human cells.

http://www.eurekalert.org/pub_releases/2009-02/embl-nfr020209.php

[mixin]

Re: Experts identify key area of bird flu virus

Here's a larger picture of the linked one above.

http://www.embl.org/aboutus/news/press/2009/04feb09/press04feb09_l.jpg

[Francoise Ramona]

Re: Experts identify key area of bird flu virus

<table class="tborder" id="post207184" align="center" border="0" cellpadding="6" cellspacing="1" width="100%"><tbody><tr><td class="thead" id="currentPost"> Today, 05:03 AM <!-- / status icon and date -->
</td> </tr> <tr> <td class="alt2" style="padding: 0px;"> <!-- user info --> <table border="0" cellpadding="0" cellspacing="6" width="100%"> <tbody><tr> <td class="alt2"></td> <td nowrap="nowrap"> lili <script type="text/javascript"> vbmenu_register("postmenu_207184", true); </script>
?diteur, Senior Moderator
</td> <td width="100%">
</td> <td valign="top" nowrap="nowrap"> Join Date: May 2006
Posts: 1,467


</td> </tr> </tbody></table> <!-- / user info --> </td> </tr> <tr> <td class="alt1" id="td_post_207184"> <!-- message, attachments, sig --> <!-- icon and title --> Re: Eurekalert - Les nouveaux r?sultats indiquent comment le virus de grippe d?tourne les cellules humaines
<hr style="color: rgb(204, 204, 204); background-color: rgb(204, 204, 204);" size="1"> <!-- / icon and title --> <!-- message --> Letters to Nature

Nature , | <abbr title="Digital Object Identifier">doi</abbr>:10.1038/nature07745; Received 10 November 2008; Accepted 22 December 2008; Published online 4 February 2009




The cap-snatching endonuclease of influenza virus polymerase resides in the PA subunit

Alexandre Dias^1,³, Denis Bouvier^1,³, Thibaut Cr?pin^1,³, Andrew A. McCarthy^1,², Darren J. Hart^1,², Florence Baudin¹, Stephen Cusack^1,² & Rob W. H. Ruigrok¹

1. Unit of Virus Host-Cell Interactions, UJF-EMBL-CNRS, UMR 5233, 6 rue Jules Horowitz, BP181, 38042 Grenoble Cedex 9, France
2. Grenoble Outstation, European Molecular Biology Laboratory, 6 rue Jules Horowitz, BP181, 38042 Grenoble Cedex 9, France
3. These authors contributed equally to this work.

Correspondence to: Stephen Cusack^1,² Correspondence and requests for materials should be addressed to S.C. (Email: cusack@embl.fr).

Top of pageAbstract

The influenza virus polymerase, a heterotrimer composed of three subunits, PA, PB1 and PB2, is responsible for replication and transcription of the eight separate segments of the viral RNA genome in the nuclei of infected cells. The polymerase synthesizes viral messenger RNAs using short capped primers derived from cellular transcripts by a unique 'cap-snatching' mechanism¹. The PB2 subunit binds the 5' cap of host pre-mRNAs^2,^3,⁴, which are subsequently cleaved after 10?13 nucleotides by the viral endonuclease, hitherto thought to reside in the PB2 (ref. 5) or PB1 (ref. 2) subunits. Here we describe biochemical and structural studies showing that the amino-terminal 209 residues of the PA subunit contain the endonuclease active site. We show that this domain has intrinsic RNA and DNA endonuclease activity that is strongly activated by manganese ions, matching observations reported for the endonuclease activity of the intact trimeric polymerase^6,⁷. Furthermore, this activity is inhibited by 2,4-dioxo-4-phenylbutanoic acid, a known inhibitor of the influenza endonuclease⁸. The crystal structure of the domain reveals a structural core closely resembling resolvases and type II restriction endonucleases. The active site comprises a histidine and a cluster of three acidic residues, conserved in all influenza viruses, which bind two manganese ions in a configuration similar to other two-metal-dependent endonucleases. Two active site residues have previously been shown to specifically eliminate the polymerase endonuclease activity when mutated⁹. These results will facilitate the optimisation of endonuclease inhibitors^10,^11,¹² as potential new anti-influenza drugs.

To read this story in full you will need to login or make a payment (see right).


http://www.nature.com/nature/journal...ture07745.html

<!-- / message -->

<!-- controls -->

</td></tr></tbody></table>