Fluoro-Sulfate-Based Covalent Inhibitors: Design Principles And Therapeutic Potential

Covalent inhibitors first recognize a biological target and can then form a chemical bond with it. Fluorosulfate groups have become of interest in medicinal chemistry because, under suitable conditions, they can take part in sulfur (VI) fluoride exchange (SuFEx) reactions with nucleophilic groups in proteins. In this process, sulfur is the reactive centre and fluoride may leave as the new bond forms. The reaction depends on the chemistry of the compound as well as the way it sits in the target protein. This review looks at the structure and proposed action of fluorosulfate-based inhibitors, including target binding, positioning of the reactive group, nucleophilic attack, fluoride displacement and formation of a covalent complex. It also discusses the main design considerations, possible benefits, limitations, therapeutic areas and questions that still need further study.