Issue Date: August 4, 2008
New Flu-Fighting Strategy
NEW STRUCTURAL information suggests an alternative plan of attack against flu viruses that targets something every strain of the flu has in common—the need to reproduce.
Two independent groups of researchers have obtained molecular views of an important interaction within the influenza virus's RNA polymerase, which plays an essential role in viral replication. The work could help researchers design a new class of flu treatments.
Existing flu medications, including oseltamivir (Tamiflu), tend to target highly variable flu proteins that can easily evade drugs through mutation of just a few amino acids. The new pair of structures describes a potential drug-binding site that is very similar among different strains of the flu, including the H5N1 avian influenza virus, says structural biologist Sam-Yong Park of Yokohama City University, Japan, who led one of the studies. Both groups' work "is highly significant because it has immediate therapeutic implications," says Harvard Medical School structural biologist James J. Chou, who also studies flu virus proteins.
Flu virus RNA polymerase has three subunits that must assemble properly in order to work. Park's multi-institution team solved the X-ray crystal structure of one subunit bound to a helical peptide fragment from another subunit (Nature, DOI:10.1038/nature07225). Their work, which centered on an analysis of a standard seasonal flu virus, expands on an earlier report from an international team of researchers led by Yingfang Liu of the Chinese Academy of Sciences and Zihe Rao of Tsinghua University, both in Beijing (Nature, DOI: 10.1038/nature07120). Liu and Rao's team examined the same interaction in an avian flu virus.
Both structures show that several α-helices in the larger subunit form a clamp that tightly grasps the peptide helix. The teams surmise that it might be possible to develop a molecule that mimics the peptide and blocks access to its binding site. This strategy might disrupt polymerase assembly and, therefore, viral replication.
"Protein-protein interactions often involve a large surface area, which can present problems for drug discovery. In this case, however, relatively few residues drive the binding," Liu and Rao's team writes in their report.
"These two papers represent the increasing global effort in finding solutions for fighting a potential avian flu outbreak," Chou says. However, he cautions, "the polymerase structure should not be considered as the holy grail of antiflu treatment." Resistant flu strains have made once-effective drugs useless, and though Tamiflu is still effective, resistance to it is beginning to emerge, Chou says. The structures are useful, he says, because they suggest a new addition to the antiflu arsenal which could be used with established drugs to stave off resistance.
- Chemical & Engineering News
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