SuFEx-enabled, agnostic discovery of covalent inhibitors of human neutrophil elastase

Significance An agnostic screen of our collection of stable sulfur fluoride exchange (SuFEx)able derivatives discovers a promising class of covalent and highly selective, elastase inhibitors. Their dormant behavior is a reflection of an exquisite sensitivity in choice of a protein reaction partner, like a “sleeping beauty finding the right prince.” Hence a special SuFEx catalysis environment is required for the perfect matchmaking event: a naturally folded protein with precise electrostatic and geometric setups, such that one of its own nucleophilic side chain ends up replacing the probe’s S–F link to become permanently covalent. In contrast, the same protein, when denatured, is incapable of being covalently modified by the same probe.