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Avian flu nucleoprotein - from basic research to drug development
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Hong Kong is attacked by virus once every few years. Some of the more serious cases include the avian influenza in 1997, the SARS in 2003 and the H1N1 swine flu this year. With a population of more than seven millions living in a small place, these viruses pose huge social and economical concerns to the city. To address the need to understand and combat these highly infectious agents, our research team has taken up the challenge of studying the proteins that are related to influenza virus. One of our focuses is on the avian flu nucleoprotein, a core protein of the virus. Nucleoprotein functions to wrap around the genetic material of influenza virus; and the virus cannot replicate and function properly without this protein.

We have succeeded in producing a large quantity of the avian influenza H5N1 nucleoprotein and obtaining the protein crystals. With the help of high energy X-ray diffraction and subsequent computer calculations, these protein crystals yield meaningful data for us to take a glance of its three-dimensional structure.

The nucleoprotein structure is in the shape of a banana. There is a "head" and a "body". In between them, there are two protruding "arms". A long "tail" region can also be visualized in the structure. The "tail" is shown to take part in the interaction among different nucleoprotein molecules.

The structure provides valuable information for identifying possible regions where nucleoprotein wraps the virus genetic materials. We then proceeded to individually remove those possible regions from the nucleoprotein structure to find out the most important region for such function. We have identified one of the "arm" regions on the nucleoprotein structure as the crucial element for reaching out to search for the genetic material of the virus and another 'arm' used to fix the genetic material on the protein in place.

"Prevention is better than cure". However, influenza virus mutates rapidly and it is difficult to completely immune from it. On the other hand, can we have a drug that can cure most if not all influenza strains? Resistance and side effect have already been found to drugs like Tamiflu. Therefore, it is urgent to develop more new and effective drugs. We may have got some clues from the study of nucleoprotein. As nucleoprotein remains mostly unchanged across different strains of influenza viruses and its role is to wrap around the genetic material, for replication and gene expression, the "arms" becomes the prime target for interfering with its functions. If some drugs could be found to block the genetic material from binding with the "arm", then the virus could not replicate or express. Another candidate region for drug target is the "tail". Perturbing the "tail" region will prevent the interaction of one nucleoprotein with another. We are in the process of finding such broad spectrum inhibitors against influenza viruses.

Professor Pang-chui Shaw
Department of Biochemistry
The Chinese University of Hong Kong