Mechanism of 150-cavity formation in influenza neuraminidase

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Nature Communications | Article Open
Mechanism of 150-cavity formation in influenza neuraminidase

Rommie E. Amaro,
Robert V. Swift,
Lane Votapka,
Wilfred W. Li,
Ross C. Walker
& Robin M. Bush

Affiliations
Contributions
Corresponding author

Nature Communications
2,
Article number:
388
doi:10.1038/ncomms1390

Received
20 April 2011
Accepted
13 June 2011
Published
12 July 2011


The recently discovered 150-cavity in the active site of group-1 influenza A neuraminidase (NA) proteins provides a target for rational structure-based drug development to counter the increasing frequency of antiviral resistance in influenza. Surprisingly, the 2009 H1N1 pandemic virus (09N1) neuramidase was crystalized without the 150-cavity characteristic of group-1 NAs. Here we demonstrate, through a total sum of 1.6 μs of biophysical simulations, that 09N1 NA exists in solution preferentially with an open 150-cavity. Comparison with simulations using avian N1, human N2 and 09N1 with a I149V mutation and an extensive bioinformatics analysis suggests that the conservation of a key salt bridge is crucial in the stabilization of the 150-cavity across both subtypes. This result provides an atomic-level structural understanding of the recent finding that antiviral compounds designed to take advantage of contacts in the 150-cavity can inactivate both 2009 H1N1 pandemic and avian H5N1 viruses.

http://www.nature.com/ncomms/journal/v2/n7/full/ncomms1390.html

 

[tetano]

Re: Mechanism of 150-cavity formation in influenza neuraminidase

UCI study points to new means of overcoming antiviral resistance in influenza


Irvine, Calif. - UC Irvine researchers have found a new approach to the creation of customized therapies for virulent flu strains that resist current antiviral drugs.

Using powerful computer simulations, UCI?s Rommie Amaro and Robin Bush created a method to predict how pocket structures on the surface of influenza proteins promoting viral replication can be identified as these proteins evolve, allowing for possible pharmaceutical exploitation.

?Our results can influence the development of new drugs taking advantage of this unique feature,? said Amaro, assistant professor of pharmaceutical sciences and computer science. The study appears online in Nature Communications.

The search for effective flu drugs has always been hampered by the influenza virus itself, which mutates from strain to strain, making it difficult to target with a specific pharmaceutical approach.

The most common clinical flu treatments are broad-based and only partially effective. They work by interrupting the action of an enzyme protein in the virus called neuraminidase, which plays a critical role in viral replication.

In 2006, scientists discovered that avian influenza neuraminidase exhibited a distinctive, pocket-shaped feature in the area pinpointed by clinically used drugs. They named it the 150-cavity.

..

http://www.healthcanal.com/immune-s...vercoming-antiviral-resistance-influenza.html