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题名:The structure of H5N1 avian influenza neuraminidase suggests new opportunities for drug design.
作者:Russell RJ, Haire LF, ..., Gamblin SJ, Skehel JJ
来源:Nature 2006 Aug 16 [abstract on PubMed] ,Nature. 2006 Sep 7;443(7107):45-9. Epub 2006 Aug 16.
URL :http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=16915235&dopt=Abstract&holding=f1000,f1000m
日期:060930
摘要:MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK.

The worldwide spread of H5N1 avian influenza has raised concerns that this virus might acquire the ability to pass readily among humans and cause a pandemic. Two anti-influenza drugs currently being used to treat infected patients are oseltamivir (Tamiflu) and zanamivir (Relenza), both of which target the neuraminidase enzyme of the virus. Reports of the emergence of drug resistance make the development of new anti-influenza molecules a priority. Neuraminidases from influenza type A viruses form two genetically distinct groups: group-1 contains the N1 neuraminidase of the H5N1 avian virus and group-2 contains the N2 and N9 enzymes used for the structure-based design of current drugs. Here we show by X-ray crystallography that these two groups are structurally distinct. Group-1 neuraminidases contain a cavity adjacent to their active sites that closes on ligand binding. Our analysis suggests that it may be possible to exploit the size and location of the group-1 cavity to develop new anti-influenza drugs.

Selected by | Todd Lowary
Evaluated 23 Aug 2006
Comments
Todd Lowary
Gunning-Lemieux Chemistry Centre, Canada
CHEMICAL BIOLOGY

Confirmation
New Finding
This paper reports the crystal structures of three group-1 neuraminidases and demonstrates that their three-dimensional structure differs from that of group-2 neuraminidases, which have been used to design the anti-influenza agents Tamiflu and Relenza. Two enzymes that process sialic acid are key to infection by influenza viruses. Haemagglutinin enables binding of the virus to human cells while neuraminidase facilitates viral release following replication therefore enabling the spread of the infection. The anti-influenza drugs zanamivir (Relenza) and oseltamivir (Tamiflu) inhibit neuraminidase, thus preventing the viral spread. These compounds were designed from the crystal structures of a subclass of neuraminidases (group-2 enzymes). In this paper, the crystal structures of three group-1 enzymes have been solved and it was shown that their three dimensional structures differ from group-2 enzymes. In particular, a different orientation of a region of the protein known as the 150-loop results in a large cavity being exposed. Interestingly, upon ligand binding this loop closes, providing a structure analogous to the group-2 enzymes. This supports the notion that Tamiflu and Relenza will be active against group-1 enzymes, albeit their mode of recognition will differ. The presence of the cavity in the group-1 enzymes opens up new possibilities for drug design for anti-viral drug design, in particular against H5N1 avian influenza, which has a group-1 neuraminidase.

http://www.f1000biology.com/article/id/1033950/evaluation

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