15 February 2008
In the UK, a parliamentary House of Lords Select Committee is undertaking an inquiry into the effectiveness of action by intergovernmental organisations to control the spread of infectious diseases. Its primary focus is on HIV/AIDS, tuberculosis, malaria and avian influenza and the Committee aims to publish its report in the summer of 2008. Diamond, the UK’s new synchrotron science facility, which began operating in January 2007, has submitted written evidence to the inquiry. Diamond will contribute to the fight against these diseases through its user programme, which gives academic and industrial researchers access to state-of-the-art macromolecular crystallography (MX) beamlines.
These MX beamlines exploit Diamond’s intense X-rays to examine crystals of biological macromolecules. The diffraction patterns from these crystals allow the determination of the 3-D structures of these molecules at the atomic level, providing insights into biological function and forming the basis for the rational design of new therapeutic agents. A class of molecules of particular interest to structural biologists is the membrane proteins. Their location makes them desirable drug targets – currently over 50% of commercially available drugs interact with membrane proteins – however they are notoriously difficult to study by MX techniques. To address this challenge, a new membrane protein laboratory has been established at the synchrotron which aims to provide world class expertise, equipment and training in the area of membrane protein x-ray crystallography whilst expanding Diamond’s suite of cutting edge MX facilities.
A number of structural research projects are currently underway by users of Diamond, contributing to the rational design of drugs against a wide variety of medical conditions and including the causative agents of the four communicable diseases identified by the House of Lords Select Committee.
HIV/AIDS represents a good example where advances in structural biology has led to effective treatments in the clinic. These include a class of drugs called HIV protease inhibitors which were developed as a result of structural data – for example, the commercially available products Viracept®, Agenerase® and Aluviran® (approved in 1999/2000)
Ongoing research at Diamond Light Source is focusing on alternative biological targets such as HIV reverse transcriptase (University of Oxford) and HIV integrase (Imperial College) – both of which are essential elements of the viral life cycle, allowing it to hijack the target cell’s survival machinery. Structural studies on these viral enzymes and interacting host proteins are providing valuable insights into the mechanisms by which the virus is able to prosper within the human cell, thus paving the way for the development of new viral inhibitor drugs.
Researcher spokesperson: Dr Peter Cherepanov (Imperial College, London) – email@example.com
Estimated worldwide TB incidence rates in 2000. The estimated incidences of HIV in TB cases are shown for each region. Courtesy of the World Health Organisation.
Tuberculosis is a major cause of death worldwide, killing over 1.5 million people each year. Whilst effective drugs for the treatment of TB exist, current therapy requires prolonged treatment regimens, often leading to the emergence of multidrug resistance. Furthermore the causative organism, Mycobacterium tuberculosis, can exist in the body in a dormant state and current drugs are largely ineffective against the latent bacterium. The publication of the complete genome sequence for M. tuberculosis in 1998 stimulated renewed efforts to seek new drug targets for TB. A number of gene products have been identified which are thought to be associated with the bacterium’s dormant state – in particular those which allow it to metabolise lipids from the host as its primary energy source.
Several academic groups have been using MX beamlines at Diamond to investigate the structure of M. tuberculosis proteins, including the Universities of Oxford, Leeds, Birmingham and Cambridge, Kings College and Birkbeck College. Dr Isaac Westwood from the University of Oxford has been leading a team looking at the structure of a particular M. tuberculosis enzyme called HsaD, which acts as a catalyst in the metabolism of cholesterol and may be a possible therapeutic target for the dormant bacterium. HsaD was the first protein structure solved on an MX beamline at Diamond Light Source to be published in a peer-reviewed journal (Acta Crystallographica, January 2008).
Researcher spokesperson: Dr Isaac Westwood (University of Oxford) – firstname.lastname@example.org
Mosquitos transmit the parasite plasmodium falciparum to humans which causes malaria.
Malaria poses an extraordinarily difficult disease for drug design because of the complicated life cycle of the parasite (Plasmodium falciparum), its interactions with different hosts and the emergence of drug resistant strains. However this means that there are many potential therapeutic targets associated with the survival of P. falciparum, and a number of studies are in progress to exploit structural information on these biological components to design effective anti-malarial drugs.
For example, groups from the Universities of Oxford and York are using Diamond Light Source to investigate the structure of a number of individual proteins from P. falciparum, including a promising class of enzymes called protein kinases, which have been shown to be good therapeutic targets in other medical applications such as the treatment of cancer. In the longer term, the key to successful malaria treatment is thought to lie in the development of vaccines, thus future MX research projects at Diamond are likely to home in on the surface proteins of the malaria parasite in order to facilitate the development of innovative vaccine strategies to protect against this disease.
Researcher spokesperson: Prof Anthony Wilkinson (University of York) email@example.com
The influenza virus exerts its pathogenicity through the action of two proteins which lie on its surface – haemagglutinin and neuraminidase. A notable example of the successful use of synchrotron technology to advance drug design lie in the development of the anti-flu drug Tamiflu® (approved in 1999) which was designed based on knowledge of the 3-D structure of neuraminidase. The structure of the Tamiflu active ingredient bound to neuraminidase was found in studies carried out at the Stanford Synchrotron in California.
Structural biologists have also studied in depth the second surface protein, haemagglutinin, (HA) which allows the virus to bind to its target cell. It is changes in this protein that in the future may allow the avian virus to bind to and infect human cells. A research programme by users at Diamond Light Source is focused on studying the structure of influenza HAs, including those from the avian H5N1 virus and from viruses extracted from human patients. This work aims to understand the effects of structural changes in the HA molecule and is therefore paramount to predicting how the avian flu virus could acquire the ability to make the jump into humans and become pandemic.
Sir John Skehel (National Institute for Medical Research ) – firstname.lastname@example.org,
Dr Stephen Gamblin (National Institute for Medical Research) – email@example.com and
Dr Elspeth Garman (University of Oxford) – Elspeth@biop.ox.ac.uk
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