Synthesis of a Stable Hydrophilic trans-Cyclooctene Amino Acid Unlocks Fast Bioorthogonal Click Chemistry for the Generation of Antibody-Drug Conjugates by Genetic Code Expansion.

Authors

Georgi R Genov, Dina Osmanović, Ines Bašić, Christine Koehler, Paul F Sauter

Published in

Angewandte Chemie (International ed. in English). Oct 29, 2026. Epub Oct 29, 2026.

Abstract

The strain-promoted inverse electron demand Diels-Alder cycloaddition (SPIEDAC), usually employing trans-cyclooctenes (TCOs) and tetrazines, represents one of the fastest bioorthogonal click reactions currently available within the bioorthogonal "toolbox". TCOs can be conveniently introduced into proteins via genetic code expansion (GCE) technology, enabling a selectable site-specific incorporation of such noncanonical amino acids (ncAAs) at predefined positions. Their application under physiological conditions, however, is limited due their inherent instability toward alkene isomerization to the unreactive cis-isomer. This has limited the use of TCO-containing ncAAs for quantitative labeling applications, for example, of therapeutical bioconjugates. In this study, we report on the synthesis and application of a stable hydrophilic TCO-ncAA for efficient production of a highly efficacious antibody-drug conjugate (ADC) via GCE and subsequent SPIEDAC conjugation.

PMID:
42952372
Bibliographic data and abstract were imported from PubMed on 29 Oct 2026.

Read full publication at:
Please sign in to see all details.

Stats

1-terrible, 9-excellent. How would you rate this publication? Sign in in to submit your rating.

Post a comment

You need to be signed in to post comments. You can sign in here.

Comments

There are no comments yet.