New Method Optimizes Membrane Protein Drug Discovery

A new method reportedly makes it easier to discover novel ligands and inhibitors against membrane proteins, which remain largely intractable to traditional approaches. The method and its applications are described in a paper published recently in Nature Chemistry.

In recent years, DNA-encoded chemical library (DEL) has emerged as a powerful drug screening technology, but it has proven difficult to use DEL to interrogate membrane proteins on live cells. To get around those difficulties, a team led by researchers at the University of Hong Kong developed a new approach that leverages DNA-programmed affinity labelling (DPAL), which utilizes a DNA-based probe system that can specifically deliver a DNA tag to the desired protein on live cells. The DNA tag then serves as a beacon to direct target-specific DEL screening.

The new method also addresses a problem associated with target abundance by using complementary sequences in the DNA tag on the target protein and the actual library, so that the library can hybridize close to the target, thereby "boosting" the effective concentration of the target protein.

"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," explained senior author Xiaoyu Li.