Expanding the range of biological systems that can be investigated and targeted by chemical biology approaches is becoming increasingly crucial to the development of novel therapeutics. Reactive electrophiles capture specific compound-target interactions, so can be leveraged as tools to facilitate the discovery and development of new medicines. Current reactive strategies suffer from limited applicability across the proteome, so expanding the range of biological systems that are amenable to targeting remains a key challenge. Sulfur(VI) fluoride (SVI-F) reactive electrophiles target numerous protein residues, so can be leveraged for the covalent modification of a broad scope of protein targets. SVI-F functionalities can exhibit diverse reactivity that can compromise the desired modification, yet to date, SVI-F functionalities have been incorporated into ligands with minimal rational design. Here, we present a three-step workflow to profile SVI-F functionalities (Figure 1) to enable the knowledge-guided application of SVI-Fs with optimal reactivity. Our SVI-F profiling workflow has identified an ideal reactivity space for SVI-F electrophiles and further enabled the reactivity prediction of novel SVI-F electrophiles. This work has examined the interplay between the reversible engagement and irreversible modification steps, and demonstrated the efficacy of SVI-F tools in both recombinant proteins and live cells, and capacity to modify an expanded range of protein targets compared to current strategies. Our SVI-F profiling workflow is envisioned to expand the utility of SVI-F functionalities in chemical biology.

Profiling sulfur(VI) fluorides as reactive functionalities that expand the ligandable proteome

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ACS Fall 2022

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