By solving the structure of the Foot-and-Mouth Disease Virus (FMDV) enzyme named '3C protease' scientists have taken an essential step towards developing protease inhibitors, a class of anti-viral drug that has proved hugely successful in controlling HIV.
The structure paves the way for their development by revealing the atomic details of the key viral enzyme that would serve as a target for drugs.
3C protease's function is to help the virus replicate itself. A drug that binds and inhibits FMDV 3C protease would stop its spread by blocking its replication and thus its ability to infect a herd.
"In an outbreak we would 'dose up' the animals and in theory they would be protected immediately," said Dr Stephen Curry of Imperial College London and senior author of the research paper, published in Journal of Biological Chemistry this week. "In contrast, vaccines take several days to have effect and that allows further spread of the disease."
"Our work is a very first step in developing an effective drug to do this. We can see what the enzyme looks like and it gives us an idea of what sort of shapes and types of molecule could bind specifically to the enzyme and block it."
The Imperial researchers are now designing a molecule to act as an inhibitor.
Together with Professor Robin Leatherbarrow of the Department of Chemistry, Dr Curry's team from the Division of Cell and Molecular Biology has probed the specificity of the 3C enzyme in the hope of developing peptide-like inhibitors, similar to those successful in tackling HIV. Professor Leatherbarrow is mapping out the key amino acid sequences that the protease snips in-between, a process called 'peptide cleavage analysis'.
"We've determined the key features of peptides that are recognised by the FMDV 3C protease. Now we can start working on making the inhibitors," said Dr Curry.
During the devastating outbreak of Foot-and-Mouth in the UK in 2001, there was much debate as to whether vaccines should be used to control the disease. They were not deployed and the government relied on mass slaughter of five million animals to bring the epidemic under control.
Protease inhibitors were developed against HIV in the 1980s and 1990s, the first going on sale in 1996. However, interactions between the drugs and the HIV virus have given rise to drug-resistant strains, reducing the treatment's effectiveness.
Although the same strategy is being adopted, Dr Curry does not foresee the same happening with an FMDV protease inhibitor due to the intrinsic differences between the diseases:
"HIV is a very long term infection, taking 10-15 years to overwhelm the body. That gives the virus plenty of time to develop resistance to anti-viral drugs. FMDV is highly contagious, much easier to get than HIV, and has a rapid onset, which is why outbreaks tend to spread so rapidly," said Dr Curry. "If you wanted to control an FMDV outbreak you could in theory swamp the livestock population with anti-viral drugs for a few weeks and hopefully eradicate the outbreak very quickly."
The 23,000 Dalton (weight) enzyme, is made of 213 amino acids, and is folded into a classic protease form, similar to those seen in poliovirus, hepatitis A virus and human rhinovirus, the major cause of the common cold.
The structure took over four years to solve, the start of research pre-dating the 2001 Foot-and-Mouth outbreak. The greatest problems came in making crystals of the 3C protease so that its structure could be solved by X-ray crystallography -- a particularly taxing task to solve for then beginning PhD student and first author of this paper, Dr James Birtley.
The work was supported by the Biological and Biotechnological Sciences Research Council, the Fleming Fund (Imperial College London), and the Medical Research Council.
Notes to Editors:
This research is published in the Journal of Biological Chemistry on 25 March.
Title: Crystal Structure Of Foot-And-Mouth Disease Virus 3c Protease: New Insights Into Catalytic Mechanism And Cleavage Specificity
Authors: James R. Birtley 1, Stephen R. Knox 2, Agnès M. Jaulent 2, Peter Brick 1, Robin J. Leatherbarrow 2 and Stephen Curry 1.
1) Biophysics Section, Division of Cell and Molecular Biology, Blackett Laboratory
2) Biological and Biophysical Chemistry Section, Department of Chemistry, Imperial College London, South Kensington Campus, Exhibition Road, London SW7 2AZ, UK.
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Journal
Journal of Biological Chemistry