Open AccessUsing sulfuramidimidoyl fluorides that undergo sulfur(vi) fluoride exchange for inverse drug discovery
Author(s) -
Gabriel J. Brighty,
Rachel C. Botham,
Suhua Li,
Luke T. Nelson,
D.E. Mortenson,
Gencheng Li,
Christophe Morisseau,
Hua Wang,
Bruce D. Hammock,
K. Barry Sharpless,
Jeffery W. Kelly
Publication year - 2020
Publication title -
nature chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 9.996
H-Index - 232
eISSN - 1755-4349
pISSN - 1755-4330
DOI - 10.1038/s41557-020-0530-4
Subject(s) - chemistry , electrophile , covalent bond , combinatorial chemistry , fluoride , nucleophile , reactivity (psychology) , drug discovery , stereochemistry , biochemistry , organic chemistry , inorganic chemistry , medicine , alternative medicine , pathology , catalysis
Drug candidates that form covalent linkages with their target proteins have been underexplored compared with the conventional counterparts that modulate biological function by reversibly binding to proteins, in part due to concerns about off-target reactivity. However, toxicity linked to off-target reactivity can be minimized by using latent electrophiles that only become activated towards covalent bond formation on binding a specific protein. Here we study sulfuramidimidoyl fluorides, a class of weak electrophiles that undergo sulfur(VI) fluoride exchange chemistry. We show that equilibrium binding of a sulfuramidimidoyl fluoride to a protein can allow nucleophilic attack by a specific amino acid side chain, which leads to conjugate formation. We incubated small molecules, each bearing a sulfuramidimidoyl fluoride electrophile, with human cell lysate, and the protein conjugates formed were identified by affinity chromatography-mass spectrometry. This inverse drug discovery approach identified a compound that covalently binds to and irreversibly inhibits the activity of poly(ADP-ribose) polymerase 1, an important anticancer target in living cells.