Extending the reach of covalent drugs

Abstract

The ability of covalent drugs to form strong bonds to protein targets tends to give them the advantage of long-lasting action. So far, covalent drug discovery has almost exclusively involved electrophilic small molecules that react with cysteine thiol groups (–SH) on proteins. The approved anticancer drug afatinib, for instance, is an electrophile that bonds covalently to a cysteine in epidermal growth factor receptor. A new study could help expand the reach of covalent drugs to nucleophiles. Cells often regulate proteins by using reactive oxygen species to oxidize cysteine thiols to cysteine sulfenic acids (–SOH). Cysteine oxidation makes thiol’s sulfur less reactive with electrophiles. About 15% of cellular cysteines are oxidized. To extend covalent drug discovery to cysteine-oxidized proteins, Kate Carroll of Scripps Research Institute Florida and coworkers recently developed a library of nucleophilic drug candidates. Compared with electrophiles, which react readily with nontarget biomolecules, nucleop...