A Step Towards Drugging The ‘Undruggable’

Researchers have developed a new way to screen potential drugs against membrane proteins, targets previously considered ‘undruggable’.

AsianScientist (Jan. 16, 2021) – Researchers in China have achieved what was once thought improbable: drugging ‘undruggable’ targets like membrane proteins in live cells. Their novel drug discovery method was published in Nature Chemistry.

From receptor proteins that receive chemical signals to transport proteins that shuffle substances across the cell, membrane proteins perform a variety of vital biological tasks. Unsurprisingly, many diseases are associated with malfunctions in membrane proteins—with over 60 percent of all FDA-approved small molecule drugs targeted towards membrane proteins. Consider the G-protein coupled receptor (GPCR) superfamily, which is targeted by 34 percent of all clinical drugs.

Despite their significance, developing drugs against membrane proteins is notoriously challenging. When isolated outside the cell membrane, these proteins tend to lose essential features and may even be deactivated.
Seeking to target membrane proteins in live cells, researchers led by the University of Hong Kong’s Dr. Li Xiaoyu refined a common industry technique: the DNA-encoded chemical library (DEL).

In DEL, each chemical compound is given a unique DNA tag that records the compound’s structural information. With these tags in place, billions and even trillions of compounds can be mixed and simultaneously screened against the target. However, it has proven difficult so far to perform DEL screening on membrane proteins on live cells. After all, cell surfaces are extremely complex and contain hundreds of different biomolecules. Moreover, membrane proteins are typically found in low concentrations, making highly specific targeting a challenge.

To overcome these hurdles, Li and his colleagues used a DNA-based probe system to deliver a DNA tag to the desired protein on live cells. These DNA tags are complementary to the tags given to the chemical compound library, allowing the screened compounds to easily locate and specifically bind to the desired membrane protein.

Demonstrating the efficiency of their method, the team screened around 30 million anti-cancer compounds against membrane proteins like the folate receptor and epidermal growth factor receptor on live cells. Not only can the team’s approach identify new drug targets in the form of membrane proteins, but it can also be used to revisit classical targets like GPCRs and ion channels within a live cell setting.

“We expect to the utility of this method is not limited to drug discovery, but also in academic research to explore challenging biological systems, such as oligomeric membrane protein complexes and cell-cell communications,” said Li.

“This technology… will cast new light on the development of high throughput screening methods, and thus facilitate the fishing of [compounds] targeting membrane proteins,” added co-author Professor Cao Yan from Shanghai’s Second Military Medical University.

The article can be found at: Huang et al. (2021) Selection of DNA-encoded Chemical Libraries Against Endogenous Membrane Proteins on Live Cells.


Source: University of Hong Kong; Photo: Shutterstock.
Disclaimer: This article does not necessarily reflect the views of AsianScientist or its staff.

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