Why did the parasites die? Understanding compound mode of action

For many parasitic diseases, we only have mediocre medicines whose ‘mode of action’ or ‘means of killing’ parasites are completely unknown. Over the years, drug discovery scientists have learned that if we understand exactly how medicines work to kill microbes, we can make medicines more effective, safer, and cheaper.

Additionally, dependence on single treatments has led to parasites gaining resistance. If we know how medicines work, we can treat patients with a combination of medicines that work in different but complementary ways. In this way, we may be able to defeat the parasite’s abilities to become resistant.

Often when we begin the search for a new medicine we test thousands of compounds to see which ones can kill the parasite (see ‘Making a Medicine: Start Here‘). These large ‘screens’ provide information about which compounds are good starting points, however they don’t give us any information about how they work. Generally, medicines work by specifically inhibiting the action of a parasite-derived protein. We call a parasite protein that interacts with a medicine a ‘target’. The best medicines work by inhibiting a ‘target’ that is critical for parasite survival. We try to select targets that are weak points in parasite biology. If our medicine is skilled (meaning it can always hit the bulls’ eye on the target) there are no ‘off-target’ side effects of the drug and we can kill parasites quickly.

Unfortunately, we don’t know what the targets of most drugs are. It seems bizarre to think that scientists don’t know how some of the best anti-parasitic medicines work, but the technology to decipher targets has only become available in the last decade.

The WCAIR Mode of Action team is tasked with identifying how compounds still in development and compounds that have already progressed to pre-clinical trials work. We have developed several technologies that allow us to find the ‘target’ of the compound. By identifying the target, we can investigate how interfering the target ultimately kills the parasite. Not every technique works for every compound. That’s why we have developed a suite of technologies that are fundamentally diverse in their approach. This integrated approach greatly increases our chances of identifying the target, and is likely the reason why we have successfully identified the mode of action of 14 compounds in our group’s first four years.

When a target is found the information is passed back to the drug discovery teams so that it can be used in the methods that help us design and build the medicine (‘See Creating the right chemistry‘). The work of identifying the target may also have uncovered new information about processes within the parasite that interest the parasitology teams or give them clues as to have to find out more about how the parasite lives. We use several innovative and cutting-edge technologies to identify the Mode of Action of medicines made in Dundee and around the world.

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