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Expedited Mapping of the Ligandable Proteome Using Fully Functionalized Enantiomeric Probe Pairs

submitted on 25.02.2019, 13:25 and posted on 27.02.2019, 21:04 by Benjamin Cravatt, Yujia Wang, melissa dix, jarrett remsberg, hsin-yu lee, marian kalocsay, steven gygi, gregory vite, michael lawrence, Christopher Parker
A fundamental challenge in chemical biology and medicine is to understand and expand the fraction of the human proteome that can be targeted by small molecules. We recently described a strategy that integrates fragment-based ligand discovery with chemical proteomics to furnish global portraits of reversible small molecule-protein interactions in human cells.
Excavating clear structure-activity relationships from these “ligandability” maps, however, was confounded by the distinct physicochemical properties and corresponding overall protein-binding potential of individual fragments. Here, we describe a compelling solution to this problem by introducing a next-generation set of fully functionalized fragments (FFFs) differing only in absolute stereochemistry. Using these enantiomeric probe pairs, or “enantioprobes”, we identify numerous stereoselective protein-fragment interactions in cells and show that these interactions occur at functional sites on proteins from diverse classes. Our findings thus indicate that incorporating chirality into FFF libraries provides a robust and streamlined method to discover ligandable proteins in cells.


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Declaration of Conflict of Interest

The authors declare competing financial interests. B.F.C. is a founder and advisor to Vividion Therapeutics, a biotechnology company interested in using chemical proteomic methods to develop small-molecule drugs to treat human disease. C.G.P. serves as a consultant for Vividion Therapeutics.