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Extending the reach of covalent drugs

Inhibitors that bond covalently with oxidized protein residues could represent a new class of drugs

by Stu Borman
April 24, 2017 | A version of this story appeared in Volume 95, Issue 17

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, nucleophiles are less promiscuous, potentially reducing side effects when used as drugs.

Carroll and coworkers have now found that five of the library nucleophiles react covalently with 1,280 unique S-sulfenylated cysteines in 761 cancer-cell proteins (J. Am. Chem. Soc. 2017, DOI: 10.1021/jacs.7b01791). One of the compounds, a pyrrolidinedione nucleophile, reacts with four protein tyrosine phosphatases, signaling proteins involved in diabetes, obesity, cancer, and rheumatoid arthritis. The researchers think this nucleophile could be a starting point for designing covalent inhibitors that target that family of enzymes.

“The work advances strategies to hit targets like phosphatases, which have historically been very difficult to drug,” comments protein-inhibitor expert Nathanael Gray of Harvard Medical School.


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