Scientists strive to make new drugs ‘like house guests from hell’

Designing drugs to be like house guests from hell – reluctant to leave, despite their host’s best efforts - may hold the key to more effective treatment of cancers and brain diseases like Alzheimer's.

Scientists continue to be frustrated by promising compounds that work well in the laboratory but ultimately fail, due to these compounds entering cells effectively but then being kicked out before they can take effect.

Researchers are, however, now recognizing that the susceptibility of compounds to so-called ‘transporter systems’ can be just as important in drug discovery as how compounds target the ‘bad’ parts of a cell and how potent they are.

Scientists meeting at the British Pharmacological Society’s Winter Meeting in London this week (14-16 December) will discuss the latest developments in the use of transporters in drug research at a special symposium.

Cells have developed special systems to take up what they want – for example, glucose and amino acids for energy and protein - and throw out what they don’t want, such as compounds that are non-food components of diet.

For example, oranges contain fructose and Vitamin C, which the cell can use, but also many other compounds that give the characteristic colour, taste and smell, but can’t provide energy or protein. Such food components are seen as ‘useless’ compounds and are pumped out of cells by naturally existing ‘xenobiotic’ transporters, which get rid of anything foreign to the cell.

This natural system, however, often thwarts the efforts of scientists working on drugs for a number of diseases. A compound can be highly potent and highly selective – in other words, very good at doing what it was designed to do and also effective in selecting the protein that is causing disease. But it can also be useless in practice, as it is thrown out of the cell very rapidly. 

When this happens in cancer cells, for example, this highly efficient clearance of the drug means the anti-cancer agent never gets a chance to perform and the cancer becomes ‘resistant’ to treatment.  Therefore, in drug development, it’s often necessary to settle for second best – such as another compound that is not so potent and not so selective but less efficiently pumped out of the cell, so ultimately more effective.

Professor Jean-Michel Scherrmann from the University of Paris, France, who will present at the symposium, is working to develop a deeper understanding of transporters at the so-called ‘blood brain barrier’ (BBB), which makes it hard to treat diseases of the central nervous system (CNS).

As well as cancer, CNS diseases can include Alzheimer's, Parkinson’s, multiple sclerosis, and Huntington's disease.

The blood brain barrier is important because the brain is essentially sealed off from the rest of the circulation by a very tight barrier between the blood in the blood vessels and the brain cells.

Many drugs cannot get through this barrier and brain tumours in particular are much harder to treat. This is because the anti-cancer drugs that work for tumours in other areas of the body, such as the bladder and the breast, and which are given by mouth or injection, can't enter the brain to hit the tumours there because the BBB keeps them out.  To add to the difficulty, there are also transporters in the BBB, pumping anything that does get through, but which is seen as foreign, straight out again.

Professor Sherrmann says that, in recent years, there have been exciting discoveries about how the genes function that control transporters in the BBB.

 “This work could ultimately help to better define how to penetrate the brain with effective drugs to treat a number of diseases,” he adds. 

‘Transporters in drug development’ is a joint symposium with British Toxicology Society. It is organised by Professor Gabrielle Hawksworth (University of Aberdeen), who will also Chair the symposium, along with Mr John Keogh (GlaxoSmithKline).


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