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05 February 2009Nature, edited by Infection Research
Promising drug target in influenza virus identified
Researchers identified a key region of the H5N1 avian influenza virus. This region is important for viral replication and could be a target for new anti-influenza drugs, two teams report in papers published in the Nature ahead of print programme.
The heterotrimeric RNA polymerase contains three subunits called PB1, PB2 proteins and PA. The two teams focused their research on the PA subunit which exact role in virus replication remained unclear.
Essential for the synthesis of viral proteins is „snatching“ a small RNA piece called cap from host cell messenger RNA by endonuclease acticivity. This cap is attached to the viral messenger RNA to use the host's proteine-synthesis. Exactly how the polymerase achieves this has remained controversial.
Stephen Cusack and colleagues of the European Molecular Biology Laboratory (Grenoble, France) studied the amino-terminal 209 residues of the PA subunit. Biochemical and structural analysis revealed strong RNA and DNA endonuclease activity. „Our results establish for the first time, to our knowledge, a unique role for the PA subunit of influenza virus polymerase and contradict the widely held view that the endonuclease active site is located in the PB1 subunit“, they write.
The team of Zihe Rao (Chinese Academy of Sciences, Beijing) reports the crystal structure of the N-terminal 197 residues of PA. Structural comparisons and mutagenesis analysis revealed an endonuclease motif. The endonuclease activity could be confirmed by functional analysis with in vivo ribonucleoprotein reconstitution, supporting the findings of Cusack's team. „The high conservation of this endonuclease active site among influenza strains indicates that PA is an important target for the design of new anti-influenza therapeutics,“ Rao et al. write.
Crystal structure of an avian influenza polymerase PA N reveals an endonuclease active site. Puwei Yuan, Mark Bartlam, Zhiyong Lou, Shoudeng Chen, Jie Zhou, Xiaojing He, Zongyang Lv, Ruowen Ge, Xuemei Li, Tao Deng, Ervin Fodor, Zihe Rao & Yingfang Liu. Nature ahead of print 05. Feb. 2009 (Vol. 457, No. 7230) doi: 10.1038/nature07720
The cap-snatching endonuclease of influenza virus polymerase resides in the PA subunit. Alexandre Dias, Denis Bouvier, Thibaut Cre´pin, Andrew A. McCarthy, Darren J. Hart, Florence Baudin, Stephen Cusack & Rob W. H. Ruigrok. Nature ahead of print 05. Feb. 2009 (Vol. 457, No. 7230) doi: 10.1038/nature07745
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