A Bioorthogonal Click Chemistry Toolbox for Targeted Synthesis of Branched and Well-Defined Protein–Protein Conjugates

Mathis Baalmann, Laura Neises, Sebastian Bitsch, Hendrik Schneider, Lukas Deweid, Philipp Werther, Nadja Ilkenhans, Martin Wolfring, Michael J. Ziegler, Jonas Wilhelm, Harald Kolmar, Richard Wombacher*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

16 Citations (Scopus)

Abstract

Bioorthogonal chemistry holds great potential to generate difficult-to-access protein–protein conjugate architectures. Current applications are hampered by challenging protein expression systems, slow conjugation chemistry, use of undesirable catalysts, or often do not result in quantitative product formation. Here we present a highly efficient technology for protein functionalization with commonly used bioorthogonal motifs for Diels–Alder cycloaddition with inverse electron demand (DAinv). With the aim of precisely generating branched protein chimeras, we systematically assessed the reactivity, stability and side product formation of various bioorthogonal chemistries directly at the protein level. We demonstrate the efficiency and versatility of our conjugation platform using different functional proteins and the therapeutic antibody trastuzumab. This technology enables fast and routine access to tailored and hitherto inaccessible protein chimeras useful for a variety of scientific disciplines. We expect our work to substantially enhance antibody applications such as immunodetection and protein toxin-based targeted cancer therapies.

Original languageEnglish
Pages (from-to)12885-12893
Number of pages9
JournalAngewandte Chemie - International Edition
Volume59
Issue number31
DOIs
Publication statusPublished - 27 Jul 2020
Externally publishedYes

Keywords

  • antibody–drug conjugates
  • bioorthogonal chemistry
  • click chemistry
  • protein ligation
  • protein–protein conjugates

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