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TB drug discovery paves way to pharmaceutical superhighway


New screening method using ‘allosteric compounds’ could dramatically increase efficiency of drug discovery.


Ribbon representation of the structure of an enzyme known as ATP-PRT from TB bacteria (blue), bound to an allosteric activator (pink).
Ribbon representation of the structure of an enzyme known as ATP-PRT from TB bacteria (blue), bound to an allosteric activator (pink).
Luiz Carvalho

The hunt for new drugs often involves checking and rechecking thousands of already identified compounds. If a compound interacts promisingly with the chosen disease target, further tests ensue.

It’s a time-consuming process with a major drawback: screening methods test compounds in isolation, and fail to account for the sometimes-confounding influence of other compounds present in the human body.

But a new approach may cut through those obstacles, dramatically improving the time and cost of discovering new drug treatments, according to scientists at the Francis Crick Institute in London. The proof of their concept, the say, is discovering a new molecule combination with the potential to treat tuberculosis without damaging host cells.

The team of researchers, led by João Pisco, report on the new screening method in a paper published in the journal Nature Communications.

The technique tests known molecules in combination with other substances – known as ‘allosteric’ compounds – revealing a much more complete picture of how the targets actually behave in the real world.

Allosteric compounds interact with target enzymes by binding to a site at a different point along the particular metabolic pathway and effecting, thus, a change in composition or shape of that enzyme. The change either boosts or suppresses its activity.

The changes induced by allosteric compounds can be beneficial or harmful: the interpretation depends on whether the enzyme in question will improve or worsen the effect of a treatment by increasing or decreasing its influence.

“Allosteric enzymes have important functions in all living things from bacteria to humans,” says co-author Luiz Carvalho, “and now we have an improved way of finding new drugs that could work by targeting them.”

The new screening method, dubbed “compound screening in the presence of an inhibitor” (CoSPI), has the potential to eliminate false starts, making screening for new drug treatments more efficient.

As proof of concept, the team took an enzyme found in TB bacteria that affects the regulation of an amino acid essential for human health.

Running it through CoSPI, the team identified an allosteric compound that dramatically increased its activity levels, effectively draining energy from the bacterium, causing its death.

The results suggest the possibility of a new drug treatment that could induce TB bacteria to self-destruct while leaving host cells intact.

“Our method allows us to find out early on how compounds interact to change enzyme activity,” says team member Cesira de Chiara. “We can find out more information in fewer experiments, which helps accelerate the drug discovery process.”

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Andrew Masterson is news editor of Cosmos.
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