New Drug Discovery Strategy Developed For Non-Druggable Drug Targets

A new drug discovery method has been developed that targets membrane proteins on live cells. The research led by Dr Xiaoyu LI from the Research Division for Chemistry, Faculty of Science, in collaboration with Professor Yizhou LI from School of Pharmaceutical Sciences, Chongqing University and Professor Yan CAO from School of Pharmacy, Second Military Medical University in Shanghai is published in the journal Nature Chemistry

As membrane proteins play important roles in biology, many of them are high-value targets that are being actively pursued in the pharmaceutical industry. The method provides an efficient way to discover novel ligands and inhibitors against membrane proteins, which is difficult to find by the traditional methods.

The Background Of Study

The membrane proteins on the cell surface perform variety of biological functions that are important for the survival of cells and organisms. Numerous human diseases are associated with abnormal function of membrane protein functions. 60 percent of all FDA-approved small-molecule drugs target membrane proteins. The largest class of cell-surface receptors, G-protein coupled receptor (GPCR) is the target of approximately 34 percent of all the clinical trials.

However, drug discovery against membrane proteins is challenging due to the special property of the cell membrane and the membrane proteins are difficult to study in an isolated form as they lose essential cellular feature and may be deactivated.

The pharmaceutical industry considered membrane proteins undruggable.

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Recently, the DNA-encoded chemical library (DEL) has emerged and become a powerful drug screening technology.

Key Findings

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The team faced two hurdles that they need to overcome to enable the application of DEL on live cells. First, as the cell surface is not a convex, locating the desired target on the cells surface is difficult. The team overcame this problem of target specificity by using a method called DNA-programmed affinity labelling (DPAL). The second challenge is target abundance as the membrane proteins exist in low concentrations which are below the required concentration needed to capture the tiny fraction of binders among billions of non-binders in a library. The team overcame this problem by using a novel strategy of 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.

The team demonstrated the performance of this method by screening a 30.42-million-compound library against folate receptor (FR), carbonic anhydrase 12 (CA-12), and epidermal growth factor receptor (EGFR) on live cells, all are important targets in anti-cancer drug discovery.

His approach can be applied to many membrane proteins for example in classical drug targets, like GPCRs and ion channels, may be studied again in a live cell setting to identify new drug discovery opportunities by harnessing the power of DEL.

Dr Xiaoyu Li said, "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.”

Co-corresponding author Professor Yizhou Li said, "This method has the potential to facilitate drug discovery for membrane proteins with the power of large and complex chemical diversity from DNA-encoded chemical libraries. This technology is an effective tool for characterising ligand-target interaction; it will cast new light on the development of high throughput screening methods, and thus facilitate the fishing of ligands targeting membrane proteins."

Source-Medindia