Small molecules, big breakthrough

August 16, 1996

Edinburgh University has joined forces with a clutch of pharmaceutical firms to carry out research that could lead to a better understanding of how small molecules interact with cellular proteins. The collaboration may also provide new insights into the origins of BSE.

The heart of the Pounds 2.5 million initiative will be the Edinburgh Centre for Protein Technology. The enterprise is being partly backed by the Government's Technology Foresight executive and firms involved include Zeneca, Celltech, Amersham International, Oxford Glycosciences and Park-Davies.

Robert Ramage, director of the centre, said that in the 20th century, treatment of disease has involved mainly the use of small molecules such as antiobiotics. Emphasis on small molecules will continue into the 21st century but Professor Ramage believes it will be accompanied by a move towards greater use of proteins as therapeutic drugs. The interaction between small molecules and cellular proteins is a key event in the action of many therapeutic drugs.

Professor Ramage, based at Edinburgh's department of chemistry, says a crucial feature of the work will be the production of "combinatorial libraries" containing a range of new small organic molecules. An important first step in drug discovery is understanding how such molecules are able to bind themselves effectively to receptors, a special kind of protein, on the outside of cells.

Successful binding of the molecule to the receptors is essential for the second step, which involves the transfer of vital biological information into the cell, to occur. The molecules act as a key and the receptors act as locks.

Professor Ramage says creating small molecules and testing the effectiveness of their ability to bind to receptors used to take a very long time. But recent advances in technology have meant the time taken to test binding has been considerably reduced. The growing availability of combinatorial libraries, especially in the pharmaceutical industry, together with robotic laboratory techniques is also helping to speed up the production of new small molecules.

These small molecules can be tested and archived. The bigger the archive the greater the chance of developing novel compounds for a wide range of applications including the development of anti-inflammatory, anti-cancer agents and new antibiotics.

Researchers recruited by Professor Ramage for the centre include Paul Barlow, Bob Baxter, Sabine Flitsch and Nick Turner. The Edinburgh group also wants to carry out a detailed study of the structure of the prion protein, a rogue version of which is believed to be the agent that causes BSE.

Professor Ramage explained that proteins are made up of sequences of the 20 naturally occuring amino acids. Their nature and arrangement determines the manner in which the protein structure is folded in three-dimensional space.

"One aim of the centre is to study what variation in the sequence of amino acids is necessary to create changes in the 3D structure of the prion protein which results in the rogue version," said Professor Ramage.

The study of how the ordering of amino acids leads to fully folded proteins is a huge area of research and much remains unknown. As well as prions, many other proteins, such as important therapeutic glycoproteins, will be studied. The Edinburgh researchers will collaborate with chemists at Sussex University and use techniques such as X-ray crystallography, nuclear magnetic resonance and chemical synthesis.

The centre will research the ability of certain proteins and enzymes to speed up chemical processes by up to a million-fold. This could help scientists design processes that generate high-value compounds such as flavours, fragrances and antibiotics that are difficult to obtain in other ways.

It will also aim to provide multidisciplinary training for protein scientists and technologists needed by industry for the next century. In order to facilitate this, secondments to and from industry will be organised.

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