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PhotoAffinity Bits: A Photoaffinity-Based Fragment Screening Platform for Efficient Identification of Protein Ligands

submitted on 31.03.2020, 14:04 and posted on 01.04.2020, 12:56 by Emma K. Grant, David J. Fallon, Michael M. Hann, Ken G. M. Fantom, Chad Quinn, Francesca Zappacosta, Roland S. Annan, Chun-wa Chung, Paul Bamborough, David P. Dixon, Peter Stacey, David House, Vipulkumar K. Patel, Nicholas C. O. Tomkinson, Jacob T. Bush

Advances in genomic analyses enable the identification of new proteins that are associated with disease. To validate these targets, tool molecules are required to demonstrate that a ligand can have a disease-modifying effect. Currently, as tools are reported for only a fraction of the proteome, platforms for ligand discovery are essential to leverage insights from genomic analyses. Fragment screening offers an efficient approach to explore chemical space, however, it remains challenging to develop techniques that are both sufficiently high-throughput and sensitive. We present a fragment screening platform, termed PhABits (PhotoAffinity Bits), which utilises a library of photoreactive fragments to covalently capture fragment-protein interactions. Hits can be profiled to determine potency and site of crosslinking, and subsequently developed as reporters in a competitive displacement assay to identify novel hit matter. We envision that the PhABits will be widely applicable to novel protein targets, identifying starting points in the development of therapeutics.


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