Tiwari, Sona, Senthil, Sathyapriya, Khanna, Shweta, Duraisamy, Santhosh, Vechalapu, Sai Kumari, Mallojjala, Sharath Chandra, Allimuthu, Dharmaraja,
Cell Reports Physical Science, 2024
DOI: https://doi.org/10.1016/j.xcrp.2024.102260
The discovery of new chemical entities for the selective modification of protein lysines is a recent interest in the development of unique covalent chemical probes. Isatoic anhydride (benzoxauracil), possessing aminophilic reactivity, was employed for the profiling of ligandable lysines in the cellular proteome. Our reactivity evaluation of benzoxauracil with proteins using mass spectral peptide mapping revealed a biased reactivity profile with nearly all the nucleophilic amino acids. The chemoselective reactivity of electrophilic tags is a key determinant of their idiosyncratic reactions. We applied the hard-soft-acid-base (HSAB) principle for tuning isatoic anhydride’s reactivity through systematic chemical modifications for lysine-dominant reactivity. We demonstrated the employability of ring-opening chemistry in isatoic anhydride as a drug delivery modality for the release of a small molecule and doxorubicin in cancer cells. Broadly, the tunable reactivity of isatoic anhydride could be leveraged for developing lysine-selective probes and drug delivery cargos.
