Salt Effect Accelerates Site-Selective Cysteine Bioconjugation
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acscentsci.6b00180.pdf
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Checksum (MD5)
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Author(s)
Dai, Peng
Zhang, Chi
Welborn, Matthew Gregory
Shepherd, James J
Zhu, Tianyu
Van Voorhis, Troy
Pentelute, Bradley L.
Date Issued
August 2016
Journal
ACS Central Science
Publisher
American Chemical Society (ACS)
Citation
Dai, Peng, et al. “Salt Effect Accelerates Site-Selective Cysteine Bioconjugation.” ACS Central Science, vol. 2, no. 9, Sept. 2016, pp. 637–46. © 2016 American Chemical Society.
Version
Final published version
Abstract
Highly efficient and selective chemical reactions are desired. For small molecule chemistry, the reaction rate can be varied by changing the concentration, temperature, and solvent used. In contrast for large biomolecules, the reaction rate is difficult to modify by adjusting these variables because stringent biocompatible reaction conditions are required. Here we show that adding salts can change the rate constant over 4 orders of magnitude for an arylation bioconjugation reaction between a cysteine residue within a four-residue sequence (π- clamp) and a perfluoroaryl electrophile. Biocompatible ammonium sulfate significantly enhances the reaction rate without influencing the site-specificity of π-clamp mediated arylation, enabling the fast synthesis of two site-specific antibody-drug conjugates that selectively kill HER2-positive breast cancer cells. Computational and structure-reactivity studies indicate that salts may tune the reaction rate through modulating the interactions between the π-clamp hydrophobic side chains and the electrophile. On the basis of this understanding, the salt effect is extended to other bioconjugation chemistry, and a new regioselective alkylation reaction at π-clamp cysteine is developed.
MIT Department
Massachusetts Institute of Technology. Department of Chemistry
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DOI of Published Version
https://doi.org/10.1021/ACSCENTSCI.6B00180
