COMMERCIAL PROFILE:A tragic example of chirality is the action of the drug thalidomide; left-handed is a powerful tranquiliser while right-handed disrupts foetal development, causing severe handicap
RESEARCH BEING carried out at UCD, funded by Science Foundation Ireland (SFI), could lead to breakthroughs in the production of new anti-viral and anti-cancer drugs. The research team, led by Declan Gilheany at the school of chemistry and chemical biology, has just received a grant of more than €1.6 million to investigate means of applying existing technologies to aid in the cost-effective, high-volume production of nucleoside drugs.
Nucleosides are an important class of drug accounting for many of the anti-viral and anti-cancer drugs currently on the market – they include the Aids drug AZT and the cold sore treatment Zovirax. What makes them different to other drugs, however, is that they only become active once they enter the targeted cells. The difficulty lies in getting them to the target and making sure they do what they are meant to when they get there.
And what makes this all the more difficult is a property shared by many organic molecules known as chirality – whether the molecule is left-handed or right-handed. In other words, two molecules with identical chemical compositions can be very different due to their shape. They differ subtly in the spatial arrangement of their atoms, in such a way that they are mirror images of one another.
In the course of routine chemistry, one is unlikely to notice the difference because most of their chemical reactions and physical properties are the same. However, chirality has significant implications in medicine and agriculture. A trivial example is the smell of limonene; the left-handed version is the characteristic aroma of lemons, while the right-handed version is that of peppermint.
A tragic example is the action of the drug thalidomide; left-handed is a powerful tranquiliser, while right-handed disrupts foetal development, causing severe handicap. Back in the 1960s, scientists were unaware of this and the drug was manufactured and administered in what was called a racemate – mixture of left and right handed molecules – with catastrophic consequences. In 1992, the US Food and Drug Administration (FDA) made it illegal to administer racemates, and today only a single type of molecule can be administered in a medicine.
Gilheany cites the painkiller Advil as a good example of chirality. “One form of the analgesic ibuprofen will make you sick as soon as it touches your tongue,” he explains. “They had to overcome this with a special coating to allow the capsule to get to your stomach before it made you sick. The ‘new improved Advil’ took out this form of ibuprofen, leaving behind only the one that acts as a painkiller.”
He explains why the same chemical can have such profoundly different actions. “Drugs have targets and it’s a bit like fitting a hand in a glove,” he says. “If the glove is left handed and you’re trying to put a right hand into it the results won’t be what you’re looking for. Biological systems are chiral and this means that the drugs we develop have to have the correct chirality if they are to work properly.”
Following the FDA decision, the pharmaceutical industry had to find some method of getting chirality, and this was neither easy nor cheap. And it is where Gilheany comes into the story.
“My own background is that I was fortunate enough to work on this problem for a future Nobel Prize winner called Sharpless in MIT back in the 1980s,” he recalls. “The problem is that it is against the laws of physics to just get one type of molecule out of a reaction – you get both. You have to put something in to cause that to happen. We used tartaric acid as a reagent back in MIT. Quinine and menthol can also be used.”
The key to the problem is whether to go through the laborious process of sorting out the left- from the right-handed molecules or, whether you can create reactions which will only produce one type. “You want to be able to create your own chirality,” says Gilheany. “But the thing you are going to put in to make that happen is going to be very expensive. Ideally you want it to be a catalyst that is used in small quantities and is recoverable and reusable.”
In a significant breakthrough at Gilheany’s lab, the team found a way to make very efficient chiral catalysts by attaching phosphorous molecules to a metal. This breakthrough led to the establishment of the highly successful campus company Celtic Catalysts. However, about five years ago Gilheany decided that it was time to get back in the lab. “I wanted to get back to science and there was a new area of drug investigation emerging known as the protide approach and several of the protide drugs include phosphorous with chiral properties.”
These are the nucleosides mentioned earlier, the smart bombs of the healthcare industry. They do not become active until they actually penetrate their target cells when they get “switched on” by a metabolic reaction.
This means that they only act where they are meant to, but the problem is that the metabolic activation is often not very efficient and the drug’s action can be quite limited. “Loads of nucleoside drugs have been tested and it is likely that lots of very useful ones have been overlooked or missed because of the inefficiency of the activation,” says Gilheany.
Essentially, the drug needs a phosphate to be added to it in the cell to be activated properly. If this does not happen, as is often the case, the drug will not work very effectively if at all. The answer lies in adding the phosphate to the nucleoside before it is administered. This has become known as the protide approach. Simple enough when it’s put that way, but very complex at a scientific level.
Firstly, simply adding a phosphate to the drug will not work as it will prevent it from permeating the cell it is aimed at. “You have to find a way of smuggling it in by disguising it within something else and then revealing itself once it is inside the cell,” Gilheany explains. “When this is done the drugs become monstrously more efficient – hundreds if not thousands of times more efficient.”
What makes all this particularly relevant to Gilheany and his team is the fact that the compound being favoured for this molecular smuggling operation is known as a P-stereogenic molecule – one with a chiral centre at the phosphorus atom; precisely their area of expertise.
“We have developed revolutionary new synthetic pathways, which allow the synthesis of the required P-stereogenic molecules without the need to resort to wasteful separation of mixtures,” says Gilheany. “We believe that this technology can be applied to the synthesis of P-stereogenic protides and the opportunity exists to significantly bolster the development pipelines of nucleoside drugs in the anti-viral and anti-cancer areas. This can be achieved by attaching phosphoramidate structures on to a range of existing nucleoside drugs and thus create new chemical entities that have a very high chance of clinical success, are far more potent and efficacious than the parent compounds – but crucially have a potential large-scale cost-effective manufacturing route.
“But we are only at the first stage of our research into the protides,” he says. “First of all we’ve got to establish if it can work and then we can move on to developing the solution. This research would be out of the question without the SFI funding. Funding like this is crucial to Ireland as it will give us the credibility in areas like this which will help us attract new investments in the future.”
