In Situ Click Chemistry Screen Facilitated by an On‐Nanoparticle DNA‐Encoded Library Identifies Highly Selective and Potent Peptoid Ligands for a Phosphatase

Capture agents that selectively bind to biological targets are indispensable tools in diagnostics, therapeutics, and biomedical research. However, discovering such capture agents, particularly for structurally conserved or challenging targets, remains a challenge. Here, we describe a protein-templated in situ click strategy enabled by a nanoparticle-based DNA-encoded library (nanoDEL) platform. The nanoDEL enables the construction and screening of vastly large, chemically diverse combinatorial libraries with high redundancy, far exceeding the scale and throughput of conventional approaches, such as one-bead-one-compound and solution-phase in situ click methods. Thus, this enables the rapid and efficient identification of high-affinity, high-selectivity ligands in a single selection round, eliminating the need for iterative screening. To demonstrate the utility of this strategy, we perfor…