Phosphorus fluoride exchange chemistry: An emerging strategy for covalent drug discovery

As a next-generation click chemistry platform, Phosphorus Fluoride Exchange (PFEx) involves the substitution of P(V)–F bonds with nucleophiles to form stable P(V)–O and P(V)–N linkages. Aryl phosphoramidofluoridates, key PFEx substrates, exhibit remarkable stability against hydrolysis and maintain integrity in complex biological environments. Despite this stability, they can react with nucleophilic amino acid residues such as lysine (Lys), histidine (His), tyrosine (Tyr), and cysteine (Cys) through proximity-enabled reactivity. Such features make PFEx chemistry a promising approach for designing novel covalent warheads. Similar to Sulfur (VI) Fluoride Exchange (SuFEx), PFEx is expected to have broad application in materials science, drug discovery, and chemical biology. In this perspective, we highlight PFEx as an emerging strategy for covalent warhead development. We begin by introducing the synthesis, stability, and reactivity of PFEx substrates. Next, we discuss proximity-enabled PFEx and its applications in creating covalent linkages with proteins under biocompatible conditions. Finally, we explore how PFEx can expand the current covalent warhead repertoire and outline key challenges and opportunities for its translation from bench to bedside.