Academia adopts pharma methods to create cheap drugs for neglected diseases

13 Jan 2009

Paul Chinnock

Source: TropIKA.net

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Professor Alan Fairlamb CBE.

It took about 20 years of trying to persuade pharmaceutical companies to turn promising advances in basic research into drugs for neglected diseases before Professor Alan Fairlamb gave up.

Fairlamb, head of the Division of Biological Chemistry and Drug Discovery at the University of Dundee, UK, says that he had once assumed that when academics made discoveries and published their research, pharmaceutical companies would scan the literature, pick up the targets mentioned and develop drugs. After all, he had discovered the antioxidant trypanothione in 1985, now known to be a key target for several drugs used to treat neglected diseases including human African trypanosomiasis (HAT), also known as sleeping sickness, one of the most neglected of diseases. It is caused by a single-celled parasite, Trypanosoma brucei.

Fairlamb, who hopes to find a better and safer drug than the existing ones which are toxic, difficult to administer or expensive, was disappointed to find that this was not the case. He managed to persuade a few companies to screen potential drugs against novel targets – the protein molecules, enzymes, or receptors that are vital to the survival of parasites but, despite his remarkable pedigree, these efforts came to nought.

“After a lot of hard work, major pharmaceutical companies agreed to do so but then would change their minds,” he says. “I realised I’d have step up to the plate and do it myself.” That is how the Drug Discovery Unit was created at the University of Dundee.

An ambitious goal

The unit specialises in plugging this particular gap – taking targets from academia, checking that they are vital for the survival of the parasite and then, ultimately, synthesising highly-specific molecules that hit those targets, thereby destroying the parasite or inhibiting its growth.

One of the most important projects being undertaken by the unit is a tropical disease initiative that has been funded with £8.1 million from the Wellcome Trust over five years. It aims to find a pre-clinical lead compound against sleeping sickness by March 2011. So far, one target has progressed pretty far towards this goal already.

“That’s quite an ambitious goal, we’re being told by the referees,” says Fairlamb. “It is tremendously exciting. If all goes well we will be ahead of schedule with this particular target.”

Crucial to the unit’s success so far, is that this academic division has actually modelled itself on pharmaceutical research principles. As Fairlamb puts it, “We have imported all of the standard techniques you’d expect to find in a pharmaceutical company into an academic setting.”

In academia, the focus of a researcher’s energy, funding and time is often on a single target or pathway. If the target fails, there are all sorts of implications, especially with respect to funding. In contrast the wages of industry researchers are not tied to single projects, and careers are not tied to a single target. Researchers are used to ditching projects that don’t work and moving onto new ones quickly, because they are used to working to strict deadlines and result-led timescales.

“They are happy to be shifted from one project to another as the occasion demands,” says Fairlamb. “That is very difficult with academics because their career path is different from industry,” he explains.

The industry-led approach means the drug discovery unit is based on a portfolio with several targets at different stages along the pipeline and its researchers are moved to the most promising projects. The unit has even drafted in experts from the pharmaceutical industry to head several vital stages of the drug discovery process including medicinal chemistry, high-throughput screening, pharmacokinetics and drug metabolism. Molecular biologists, entomologists and crystallographers have been recruited to feed targets into the discovery pipeline.

The differences between academia and the industry even extend as far as the molecules that are synthesised to hit the target. The group has gathered together 64,000 molecules to test against targets. Academics do not normally have access to such an enormous amount of molecules.

In addition, says Fairlamb, many academic chemists are often looking for the most innovative, novel and intricate molecules to knock out a target, because they won’t find funding otherwise.

In contrast, the unit is looking for the simplest molecules and particularly those that have already been tested on other indications. That’s because the resulting drug – aimed at some of the poorest people in the world – will be much cheaper than one containing a complex synthesis.

A key strength of the unit is being able to decide in advance which molecules might make the best drugs. The group has analysed hundreds of thousands of molecules already – ditching many that do not adhere to strict criteria associated with the type of molecules that are more likely to become drugs. For instance, it abandons any molecules that do not adhere to the so-called ‘Lipinski rule of five’ – a set of criteria which, if they are not met, indicate that a compound is unlikely to be an effective oral drug in humans.

“These kinds of constraints normally don’t normally enter into the thinking of someone carrying out synthetic chemistry in an academic lab,” he says. “They are looking for things that they can publish and are often looking for drugs which are novel and difficult synthesise, not simple, straightforward, cheap and easy ones”.

It works like this

The drug discovery unit, two-thirds of which is primarily supported by the Wellcome Trust’s neglected diseases funding, identifies targets from literature published throughout the world and tests these using several genetic and chemical tests. The test results determine whether a potential target is indeed vital to the survival of a parasite by determining whether the parasite will survive without it.

One method, called gene knock-out, for instance, replaces the gene that encodes for that particular target with a drug-resistant gene. Once that drug-resistant gene has been established in some parasites within a group, the unit tries to knock them out using the precise drug to which that gene is resistant. If those parasites with the drug-resistant gene remain alive while the others die, it is a fair bet that the target is essential to the survival of the parasite.

It is quite a crude method, so the unit also uses chemicals to selectively knock out the target. The researchers also test different compounds on the target. They ensure that the most promising ones selectively kill the parasite – in other words that the chemical will not also destroy the human cells with which it comes into contact. The unit also develops assays – chemical markers which help identify whether the target has been successfully inhibited.

Essentially the group gradually ups the obstacles the drug molecule has to surmount in order to kill the parasite effectively.

Medicinal chemists begin the systematic process of trying similar compounds, analysing and modifying the structures of such molecules- chemical group by chemical group – to determine which configuration has the greatest effect on the parasite. Later, they test how stable the molecules are when exposed to various liver enzymes. This helps them determine whether the mammalian metabolism will eat up the drug before it reaches the target.

“We try to see if there is any correlation between different structural type and potency and then we can say this is not a one-off wonder unlucky strike,” says Fairlamb.

Sometimes finding new drugs might even lead to new targets. On other occasions the targets do not work. Dubbed ‘no gos’, many are handed back to the academic research group with advice on what type of research might be necessary to help them become more successful targets.

Economics

The biotech model has yielded some pretty good results so far. Several compounds have been evaluated and four compounds are ready to progress to the lead optimisation stage, where molecules are improved to ensure they remain stable within animal models.

But this is where the reality of the economics behind research and development has kicked in. Limits in funding mean that instead of concurrently working on all the most promising compounds, Fairlamb says all hands are now on deck to progress the single compound which has reached the lead optimisation stage.

“We only have a limited resource £8.1 million. That in actual fact means that we’ve had to put a huge amount of our resource to this single lead optimisation project and other projects are parked and we can’t progress them,” he says.

The group would like to double the number of medicinal chemists working in-house so that they can concentrate several molecules at the same time. Fairlamb says he would also like to focus on the other neglected diseases covered by the grant – namely visceral leishmaniasis and Chagas’ disease. Together these diseases cause 140,000 reported deaths and millions of disabilities every year. However, the unit just doesn’t have the funds.

This is unfortunate, since there is genetic evidence that many of the targets validated for HAT are also valid targets for leishmania and for T.cruzi, which causes Chagas’ disease.

That is not to say the same drug would work for all three diseases. Professor Fairlamb believes that it is entirely likely that the molecules may just need work at the lead optimisation stage to modify molecules to target specific areas of the body. For instance sleeping sickness requires a drug that targets the blood and lymphatic circulatory system and crosses the blood brain barrier. Leishmaniasis, on the other hand, requires a drug that can reach the macrophages within the liver and spleen where leishmania parasites reside.

As a result of funding shortages, the unit is in talks with pharmaceutical companies to perhaps hand over a few candidates that have reached the stage where both the target has been validated and a ‘hit’ discovered. The drug companies can then use their specific skills to hone these molecules into drugs.

“We’ve removed a lot of the potential risks of failure early on,” he says.

That said, there is also a hope that the unit will be able to do much of this work itself in future. By working on some other more commercially viable diseases, it may be able to generate funds for more neglected disease research.

Replication

That model could then be replicated all over the world says Professor Fairlamb, including disease-endemic countries. That depends on success in this project, however. “People are watching very closely to see if it works and if it does hopefully others will spring up,” he says.

Indeed a number of other organisations have gone down this research route. A number of institutions from the University of San Francisco, UCLA and North Carolina, to WEHI in Australia are all establishing networks of researchers to plug the same gap. However, Fairlamb says that different elements of the drug discovery puzzle are often so far away from each other as to introduce inefficiencies. In contrast at Dundee, everything is in-house and as a result things proceed far more quickly, he says.

But there’s one part of the puzzle that is not dependent on pharmaceutical involvement. It is challenge for the academic research community, says Professor Fairlamb.

“The challenge now is for academics to find more molecules for us to process. We’re running out of targets and that is certainly an important issue,” he says.

More information on Professor Fairlamb and his work is available on his personal website.

Key questions

Briefly, what are the priority concerns of your organisation?
To complement the pharmaceutical sector by addressing areas of unmet need and novel methods of drug discovery.
And, more precisely, what goals have you set?
To get a molecule to the preclinical stage by 2011.
What are the main challenges outstanding?
Funding, finding new targets.
Which other organisations will you be working with most closely?
Academic institutions with targets and pharmaceutical companies that may want to take over leads.