Virus structure pockets potential new drug treatment

EV71 virus
Electron density map for HEV71 with potential drug (green) bound in the pocket of the virus.

A new virus inhibitor could be basis of a drugs to treat hand, foot and mouth disease, and point the way towards treatments for other viruses including polio and the common cold. The discovery illustrates the power of an approach based on understanding the structure of key biological molecules in targeted drug design.

Researchers from the Structural Biology Division (STRUBI) at Wellcome Trust Centre for Human Genetics worked with colleagues from Beijing, Leeds and Innsbruck to develop the new inhibitor.  It targets a group of viruses responsible for hand, foot and mouth disease, especially the EV71 virus. This viral group causes numerous epidemics in children, mainly in Asia, with roughly 10 million cases reported every year in China alone.  Symptoms are usually mild but in some cases the disease can prove fatal - the Chinese government reported over 900 deaths in 2010. The disease is currently untreatable and is a major global threat to public health.

This discovery, published in Nature Structural and Molecular Biology, may also have important implications for combating other diseases. Hand, foot and mouth disease is caused by several closely related viruses, and the new compound is effective against all of these. Poliovirus and many of the viruses responsible for the common cold also belong to the same group of viruses, the enteroviruses.

Luigi & Liz
Luigi de Colibus and Elizabeth Fry of the STRUBI team

Professor Dave Stuart, Director of STRUBI and Life Science Director at Diamond Light Source near Didcot, who worked on the new inhibitor, explains: 'By targeting a structural feature also found in related viruses, it should be possible to devise similar therapeutics to target them. Within the field, I am aware of one company that is already making progress in targeting the major common cold virus. Our work is still at an early stage, but we are working with academic groups in China to take the inhibitor forward.'

The new drug treatment, which so far has been tested only in isolated cells, was created following earlier studies that revealed the three-dimensional structure of the EV71 virus and analysed how that structure related to its ability to infect cells. The structure was solved at Diamond, the UK’s national synchrotron, in 2012. After this, scientists collected further data to determine how the virus changes shape to enter the host.

Enteroviruses are part of a larger family of viruses called picornaviruses. These viruses have an outer shell which, once inside a host cell, breaks apart releasing the genetic material of the virus into the cell. When they determined the virus structure, the team saw a small pocket inside the virus where a drug might fit. The team has identified a very potent molecule that fits into this pocket and disables the mechanism by which the viral shell breaks open, thus stopping the virus in its tracks by making it unable to infect the host.

This research is still in its early stages, and there is a considerable way to go before the drug treatment is available on the market.  However, the speed with which this development has come about demonstrates the vast potential of structure-based drug design, and the remarkable capabilities that are now at scientists’ disposal in the fight against disease.

De Colibus, Luigi et al. More-powerful virus inhibitors from structure-based analysis of HEV71 capsid-binding molecules,  Nature Structural & Molecular Biology. Published online 09 February 2014. doi: 10.1038/nsmb.2769.