Covalent molecules have emerged as next-generation therapeutics and as powerful tools for perturbing fundamental biological processes. Chemical proteomic methods to screen for reactive proteinaceous amino acids have transformed small-molecule discovery pipelines, but their application remains mostly limited to sites where reactive cysteines and lysines are present. Here we report a ninhydrin-based warhead that selectively modifies arginine residues, thus expanding the repertoire of amino acids targetable by covalent molecules. These studies uncovered potential modification sites on disease-relevant proteins, including reactive arginines within catalytic sites that are essential for function. By endowing a reversible small molecule inhibitor of cyclophilin A with a ninhydrin warhead, we achieved selective, covalent engagement, and attenuation of enzymatic activity, highlighting the potential for targeting arginines in future therapeutic development campaigns.

DNA encoded focused library has became an efficient strategy for hit identification and hit to lead optimization for specific target protein. However, the design and synthesis of target focused library is still a challenge for many protein targets. Integrating DEL with chemoproteomics could be an effective and practicable strategy for the target focused library technology development. This talk will highlight recent advancement of the technology integration between DEL and other drug discovery technologies such as FBDD and chemoproteomics for the reversible and covalent Inhibitors discovery. 

Primary DNA-encoded library (DEL) screens identify binders from millions of related compounds, but translating sequencing readouts into actionable SAR requires a systematic approach. This talk describes a practical method for extracting positive and negative SAR directly from primary DEL data and applying it to early hit optimization. Case studies illustrate the approach, which is implemented in a web-based platform integrating DEL SAR and analyses for early, data-driven decision-making.