Journal
NATURE CHEMISTRY
Volume 13, Issue 1, Pages 77-+Publisher
NATURE RESEARCH
DOI: 10.1038/s41557-020-00605-x
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A method has been developed to label membrane proteins with a DNA tag, allowing for the selection of DNA-encoded chemical libraries against endogenous membrane proteins on live cells. Screening of a 30-million-compound DEL against folate receptor, carbonic anhydrase 12, and epidermal growth factor receptor on live cells demonstrated the versatility and efficacy of this method.
Membrane proteins on the cell surface perform a myriad of biological functions; however, ligand discovery for membrane proteins is highly challenging, because a natural cellular environment is often necessary to maintain protein structure and function. DNA-encoded chemical libraries (DELs) have emerged as a powerful technology for ligand discovery, but they are mainly limited to purified proteins. Here we report a method that can specifically label membrane proteins with a DNA tag, and thereby enable target-specific DEL selections against endogenous membrane proteins on live cells without overexpression or any other genetic manipulation. We demonstrate the generality and performance of this method by screening a 30.42-million-compound DEL against the folate receptor, carbonic anhydrase 12 and the epidermal growth factor receptor on live cells, and identify and validate a series of novel ligands for these targets. Given the high therapeutic significance of membrane proteins and their intractability to traditional high-throughput screening approaches, this method has the potential to facilitate membrane-protein-based drug discovery by harnessing the power of DEL. A method to label membrane proteins with a DNA tag has been developed that enables the selection of DNA-encoded chemical libraries against endogenous membrane proteins on live cells. As a demonstration, a 30-million-compound DNA-encoded chemical library is screened against folate receptor, carbonic anhydrase 12 and epidermal growth factor receptor on live cells.
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