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The building blocks of life

13 October 2005

The vast majority of life processes result from the binding of a protein molecule to another molecule. Understanding these interactions is the key to life itself.

The modern field of structural biology originated in the 1940s with Linus Pauling (1901-1994), the only person ever to receive two unshared Nobel Prizes - for Chemistry in 1954 and for Peace in 1962. Often considered the 'founding father' of molecular biology, Pauling pioneered the structure-based approach to the study of biological systems that has formed the basis for most subsequent advances in understanding the molecular mechanisms of biological systems.

The basic premise underlying structural biology is that all life processes can be described by a variety of molecular processes. Therefore, in order to understand either a disease or normal functions of the body, it is necessary to first break down those functions into the actions of individual protein molecules, and then to determine the 'shape' of each of these proteins.

Proteins are the principal constituents of all cells. They serve as enzymes, structural elements, hormones, etc, and are involved in oxygen transport, muscle contraction, electron transport and various other activities throughout the body. Twenty different amino acids are commonly found in proteins and each protein has a unique, genetically defined sequence of amino acids which determines that protein's specific shape and function. But because a protein molecule is quite large, about 90 per cent of its function is defined by its shape, so under-standing function means having a clear picture of the protein's shape. Through the study of protein structure, primarily using protein X-ray crystallography to determine its three-dimensional shape, Brady's group aims to probe crucial biomolecular interactions, central to a variety of diseases, with a view to using this information to accelerate the development of new drugs.

It is only in the past decade that this rather academic pursuit has reached a level of understanding that can be exploited

In normal biological function a protein will bind to another molecule, designed to fit into a specific location on the protein's surface, rather like a key fitting into a lock. If the second, much smaller, molecule (the key) is the right shape to fit into the location (the lock), they will lock together and that will lead to a chemical change - a signal. That passes information on to the next molecule, and the next one, and so on until eventually your arm moves, for example. But what if you have a headache and wanted to stop the pain? In this instance the two molecules lock together but this leads to a pain signal which sends you off to the medicine cabinet for some aspirin. Since drugs are simply small molecules, they also bind to, or interact with, the larger proteins. In this case the aspirin molecule blocks the location filled by the 'pain' molecule so it cannot fit back in and cause further pain - headache goes away.

Until recently, when a new drug was needed to combat a particular disease, drug companies took a rather hit-and-miss approach to identifying which of the many millions of chemical combinations available might be appropriate as a drug. Put simply, they would culture the pathogen, grow it and then throw each chemical in, one at a time, and see which one killed it. Nowadays things are more sophisticated. Take Alzheimer's Disease that Brady's group work on - in collaboration with David Dawbarn's group in the Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology. The first question they ask is "What parts of the body go wrong in Alzheimer's Disease?" They then focus on the molecules that govern those functions. But before they can understand what is going wrong with those molecules they first need to understand what their normal state is - their normal shape.

Once the structure has been determined, they identify which parts of its shape are important to its action. These locations then become the target (the lock) for suitable drugs. Using a computer they computationally 'test' which of the millions of drugs available might fit the target. The computer ranks them by how well they fit and identifies the ones most likely to work. These can then be chemically tested to reduce the numbers even further. At that point a pharmaceutical company may step in and, based on the information provided by such groups, 'design' a drug that will either keep the molecule in its normal state, or replicate the function that is failing. It is obviously a much more complex process than it sounds, but Brady believes the corner has been turned in the past ten years and that all new drugs developed in five or ten years' time will have some element of this design process.

The first question we ask is 'What parts of the body go wrong?'

Another disease members of Brady's group study is malaria. Malaria is caused by a tiny parasite that infects humans bitten by a mosquito carrying the parasite. In this instance they examine the components that make up the normal life-cycle of the parasite. But because this parasite only infects humans, it makes it complicated to develop drugs because they cannot be tested on animals. There are equivalent parasites that infect rats, for example, but while they are very similar to the one that infects humans, they are not quite the same. Thus there is always the dilemma that the drug might work very well against the parasite in rats but not in humans. So when the drug company trials them in humans, it may not have quite the right effect and might need to be modified in some way.

Something similar happened to Brady's group a few years ago when a new type of drug it had designed and developed in collaboration with GlaxoSmithKlein had to be shelved. But fortunately another compound picked up in their studies turned out to act against a completely different target to the one they were targeting, and has proved extremely effective in killing the parasite. This compound is now entering clinical trials as a new anti-malarial drug. Developing a new drug takes a very long time, 15 years on average, and is extremely expensive - one drug can cost billions of dollars to develop - but it is good to know there is still room for an element of serendipity now and then.

Leo Brady/Biochemistry

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