Zhihong Li, Hsiao-Kuei Tsai, Adam H. Libby, Michael W. Founds, Olivia L. Murtagh, Madeleine L. Ware, David M. Leace, Wesley J. Wolfe, Phillip W. Gingrich, Bissan Al-Lazikani, Chin-Yuan Chang & Ku-Lung Hsu
Nat Commun (2026).
https://doi.org/10.1038/s41467-026-73407-3
Purines are essential bioactive molecules that interact with a large fraction of the human proteome. Despite their importance, the scope of actionable purine-binding pockets for ligand discovery remains limited. Here, we develop a quantitative chemoproteomics platform using sulfonyl-purine (SuPUR) chemistry to produce a massive and functional map of the human purine interactome. The SuPUR platform captures 31,000+ targetable tyrosine and lysine sites, representing the most comprehensive beyond cysteine chemoproteomics database for enabling protein ligand discovery. SuPUR ligands that bind through a regioselective fashion serve as enabling starting points for developing potent (nanomolar) and proteome-wide-selective modulators of enzymatic and protein-protein interaction function. Phenotypic screening identifies a site-specific (Y237) and regioselective SuPUR ligand of ACAT2 to reveal an unexpected metabolic dependency in cancer cells. A crystal structure of SuPUR ligand-bound ACAT2 reveals the purine group binds deep in the CoA pocket forming key interactions with catalytic residues via a water bridge to guide future structure-based ligand design.
