At the frontier of drug discovery, a new approach to targeting the toughest diseases using cyclic peptides.
Over the past decade, the number of new drug approvals has plateaued. This is despite growing investment in drug discovery, and a deeper knowledge of which processes or proteins to target.
A major reason for the plateau is that many of the most promising targets are also very difficult to develop drugs for. “Mostly, drugs have been developed for the low-hanging fruit,” says the Crick’s Louise Walport. “Now we need to go after the harder targets – those that play a key role in disease but are extremely difficult to work with.”
Much of the challenge lies in the molecular targets themselves. Many disease-related proteins, including those involved in cancer and neurodegenerative disorders, were for a long time considered ‘undruggable’ using conventional techniques.
That can be for several reasons. Some proteins are inherently unstable, making them hard to work with. Others are located in parts of the cell that are hard to reach with drugs. Yet more lack the well-defined 3D pockets that traditional drugs bind to.
Targeting these proteins requires solving multiple challenges.
One major challenge stems from the nature of the targets. Early drug development typically involves isolating and purifying the target protein, then testing millions of compounds to find ones that bind to it. But purifying tricky targets is often impossible, due to their unstable nature.
A second lies with ‘traditional’ drugs. Most drugs available today fall into two main categories: ‘small molecule’ drugs, and biologics.
Small molecule drugs – for example, statins or aspirin – are relatively simple, inexpensive chemicals that usually bind to pockets on target proteins. However, their small size means they can’t easily bind to proteins that lack defined pockets, causing side effects and necessitating relatively high doses.
Biologics are larger and more complex – usually entire proteins, such as antibody-based drugs or hormones like insulin. While they are much harder to get into cells, they tend to be more specific, resulting in fewer off-target effects, and can bind to more challenging targets.
Louise’s team, in the Crick’s Protein-Protein Interaction lab, are trying to tackle these problems. They’re working with a promising new class of drugs, known as cyclic peptides – small, protein-like fragments that combine the best qualities of small molecules and biologics. Importantly, they can bind to much smoother surfaces making them particularly well-suited to tackling ‘undruggable’ targets.
To solve the ‘purification problem’, Louise’s team are using a cyclic peptide discovery approach, called mRNA displays, in a novel way which eliminates the need for purification altogether.
First, they genetically engineer cells to make high levels of a given target. Then, they produce a collection of trillions of different cyclic peptides, each one linked to a unique short fragment of RNA, allowing the sequence to effectively act as a ‘barcode’ for each peptide.
Finally, they crack open their engineered cells and expose their contents to their vast collection of labelled cyclic peptides.
“If a cyclic peptide binds tightly to the target, we can identify it by reading its RNA barcode,” Louise says. “The advantage of this method is that we don’t need to purify the target at all. We’re finding cyclic peptides that stick to it in its natural, biologically relevant form.”
This is more than just a technical tweak. In avoiding purification, the team sidesteps a process that often strips proteins of their natural shape. For complex targets, maintaining a realistic cellular environment is key. “Many promising cancer targets, such as proteins that regulate gene activity, have disordered regions that make them nearly impossible to purify,” Louise explains. “For years we’ve called these targets ‘undruggable’, but that’s only true within the limits of traditional drug discovery. That’s no longer the case.”
Now that her team has demonstrated proof of principle, they plan to apply the method to proteins involved in diseases with unmet clinical needs, such as hard-to-treat cancers. They want to refine the process to work with proteins produced at normal levels, and expand the technique to cell surface targets, potentially broadening the technology’s reach.
The approach taken by Louise and her team is one of many exciting new innovations that could mark a turning point in modern drug discovery – one where the word ‘undruggable’ becomes a thing of the past.
Science from inside the Crick.
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