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Download filePyrocinchonimides Conjugate to Amine Groups on Proteins via Imide Transfer
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posted on 30.04.2020, 14:09 authored by Mark B. Richardson, Kristin N. Gabriel, Joseph A. Garcia, Shareen N. Ashby, Rebekah P. Dyer, Joshua K. Kim, Calvin J. Lau, John Hong, Ryan J. Le Tourneau, Sanjana Sen, David L. Narel, Benjamin B. Katz, Joseph W. Ziller, Sudipta Majumdar, Philip G. Collins, Gregory A. WeissAdvances in bioconjugation,
the ability to link biomolecules to
each other, small molecules, surfaces, and more, can spur the development
of advanced materials and therapeutics. We have discovered that pyrocinchonimide,
the dimethylated analogue of maleimide, undergoes a surprising transformation
with biomolecules. The reaction targets amines and involves an imide
transfer, which has not been previously reported for bioconjugation
purposes. Despite their similarity to maleimides, pyrocinchonimides
do not react with free thiols. Though both lysine residues and the N-termini of proteins can receive the transferred imide,
the reaction also exhibits a marked preference for certain amines
that cannot solely be ascribed to solvent accessibility. This property
is peculiar among amine-targeting reactions and can reduce combinatorial
diversity when many available reactive amines are available, such
as in the formation of antibody–drug conjugates. Unlike amides,
the modification undergoes very slow reversion under high pH conditions.
The reaction offers a thermodynamically controlled route to single
or multiple modifications of proteins for a wide range of applications.