One molecule: multiple lifecycle stages - Universtiy of Dundee's perspective

2014
Prof. Ian Gilbert, Head of Chemistry & Dr Kevin Read, Head of Drug Metabolism and Pharmacokinetics, University of Dundee, UK

This molecule has caused a stir among researchers the world over. DDD498 has potent activity against multiple stages of the malaria parasite’s lifecycle, giving it the potential to cure and stop the spread of the disease as well as protect people, all in a single-exposure.

In recognition of the molecule’s promise and the dedication of the team at the Dundee DDU, the project has been named MMV Project of the Year 2014. Project Leaders Prof. Ian Gilbert, Head of Chemistry (seated 3rd from the right) and Dr Kevin Read, Head of Drug Metabolism and Pharmacokinetics (seated 3rd from the left) explain how the discovery was made and their experience of working with MMV.

1. How was the compound discovered?

At Dundee’s Drug Discovery Unit we have a strong interest in neglected tropical diseases. So when MMV approached us to test one of our compound libraries against the malaria parasite, we were happy to participate. A total of 4,700 compounds were screened, giving us 11 active chemical series. MMV was already working on some of them. We began chemistry work on four series that no one was yet researching. After several cycles of design, compound preparation and testing, we identified DDD498 from one of the series.

2. What were the biggest challenges you faced and how did you overcome them?

The compounds were very much early stage hits when we began working on them. Much of the early work focused on improving the characteristics of the molecules to make them more drug-like. For example, one of the challenges we had to overcome was that the early leads had poor membrane permeability, meaning that as drugs they would be poorly absorbed in the body.

We also needed to improve the activity of the compounds against the parasite that causes malaria. As with any compound from a phenotypic screen,you do not know how it is binding to its target, so there’s always the challenge of understanding which is the best way to optimize the compound.

To overcome the challenges, we had a very focused campaign; we were strict about what we made in terms of chemistry and used a series of assays to eliminate compounds that would not make the cut.

3. What has it been like to work with MMV on DDD498?

It has been a very open collaboration – a true partnership. It’s been extremely valuable on many different levels: first of all, having regular interactions with the team at MMV, particularly Dr Paul Willis and Sir Simon Campbell’s advice on which assays and experiments to conduct, and to really question what we were doing. Second, having access to the assays for the different stages of the lifecycle that MMV has put in place was essential for understanding the properties of the compounds.

Most importantly, MMV brought focus to the project. MMV’s target product profiles, target candidate profiles and progression criteria have been really critical in guiding what we have done. It’s a well thought out process of what you really need to do to develop a compound, and accelerates the research process in a focused way, while ensuring critical questions are answered.

Without all of this, it would have been very lengthy and challenging to get to where we are today.

 


1. Phenotypic screen: compounds are tested for their activity against the whole parasite to identify those that cause the desired biological change, in this case parasite death.