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Helping drugs get around: research points way to more effective delivery of medicine around the body


For immediate release
Thursday 13 October 2005

New research showing how drugs stick to a key protein in the bloodstream could help to create drugs that are delivered more effectively to organs in the body.

Illustration of phenylbutazone (blue) and indomethacin (yellow) bound to human serum albumin in the presence of fatty acid (grey and red spheres)The research, published tomorrow in the Journal of Molecular Biology by scientists at Imperial College London, gives a vital insight into how a large number of drugs are impeded from reaching their targets by the protein Human Serum Albumin (HSA).

HSA is found at high concentrations in blood plasma and its primary function is to transport molecules of fat around the body. The protein also binds tightly to a wide range of different drugs, preventing them from travelling to their destination.

Scientists have produced detailed three-dimensional images showing how HSA binds twelve different drugs including ibuprofen, diazepam and warfarin. This information should help scientists to modify the structures of drugs to improve their effectiveness.

Dr Stephen Curry Opens in new window, lead researcher on the study from Imperial's Biophysics Group, said: "This is the first time we have been able to see high resolution images of HSA interacting with different drugs. Working out which features of HSA are responsible for binding drugs may make it possible to change the design of the drugs so they cannot be bound so easily."

HSA's ability to bind a variety of drugs often presents a serious problem during the development of new medicines. If a drug binds too tightly to HSA, it can get trapped in the bloodstream, meaning higher doses are needed to ensure that the drug's benefits are felt. Ideally, doses should be as low as possible to reduce the risks of toxicity or other side-effects.

Dr Curry adds: "Usually drug companies want to prevent HSA from limiting the concentration of drug being released into the body. Our new information should help them to design features into new drugs to achieve this. However, sometimes the binding properties of HSA can be useful if you want to create a reservoir of drug that can be released slowly and our results should help here too."

The structures of the HSA-drug complexes were determined using X-ray crystallography, a complex and delicate procedure whereby small protein crystals are grown after adding each drug to a purified preparation of the protein.

Scientists then work out the detailed atomic structure, showing how the drug binds to the protein, by shining x-rays onto the crystal and analysing how these are scattered. HSA is a particularly difficult protein to crystallise because it is a flexible molecule.

This is the first time that scientists have succeeded in completing a survey of the binding modes of a range of drugs, although HSA's structure has been known for over 10 years.

The results reported in the paper are the result of more than five years' work by a number of Imperial students and postdoctoral scientists in Dr Curry's team, who have benefited from collaborations with scientists in Japan, the US, and Denmark. This work was funded by the Wellcome Trust and BBSRC.

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For further information please contact:

Laura Gallagher
Press Officer
Communications Division
Tel: +44 (0)20 7594 6702
Mobile: +44 (0)7803 886 248
E-mail: l.gallagher@imperial.ac.uk

Notes to editors:

1. "Structural Basis of the Drug-binding Specificity of Human Serum Albumin" Journal of Molecular Biology (2005) 353, 38-52. 14 October.

2. Consistently rated in the top three UK university institutions, Imperial College London is a world leading science-based university whose reputation for excellence in teaching and research attracts students (11,000) and staff (6,000) of the highest international quality.
Innovative research at the College explores the interface between science, medicine, engineering and management and delivers practical solutions that enhance the quality of life and the environment - underpinned by a dynamic enterprise culture.
Website: www.imperial.ac.uk

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