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New Linkers Might Provide Highly Stable Protein-Drug Conjugates

Methylsulfonylphenyloxadiazole compounds are selective for cysteine residues and last longer than maleimide counterparts

by Carmen Drahl
October 14, 2013 | APPEARED IN VOLUME 91, ISSUE 41

Credit: Courtesy of Shigehiro Asano
Conceptual drawing of a protein conjugate made with a methylsulfonylphenyloxadiazole.
Credit: Courtesy of Shigehiro Asano
Conceptual drawing of a protein conjugate made with a methylsulfonylphenyloxadiazole.

Two antibody-drug conjugates are on the market today, and both of those targeted cancer therapies involve a maleimide, a moiety that readily reacts with thiols. Maleimide linkages aren’t always desirable because they can break apart and recombine with reactive groups in other biomolecules in the body. A team at Scripps Research Institute, La Jolla, Calif., now reports compounds—methylsulfonylphenyl­oxa­diazoles—that complement maleimides by producing a more stable protein-drug linkage (Angew. Chem. Int. Ed. 2013, DOI: 10.1002/anie.201306241). Narihiro Toda, Shigehiro Asano, and Carlos F. Barbas III took inspiration from a heterocyclic reagent that selectively blocks protein thiols. They synthesized a family of similar molecules and, working at physiological pH, determined that methylsulfonylphenyl­oxa­diazoles are selective for cysteine thiols over other reactive moieties in proteins. They made protein conjugates with methylsulfonylphenyl­oxa­diazoles and found that the conjugates were more stable than the corresponding maleimides in human plasma. Researchers’ excitement about drug conjugates has led to several reports of new linkers. The Barbas team adds a brand-new approach that researchers should keep in mind, says Peter D. Senter, vice president of chemistry at the antibody-drug conjugate firm Seattle Genetics. Sigma-Aldrich is commercializing the technology.



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