A Dual-Purpose Non‐Canonical Amino Acid for the Expanded Genetic Code: Combining Metal‐Binding and Click Chemistry

Graham J. Day, Andrey V. Zaytsev, Richard C. Brewster, Valery N. Kozhevnikov*, Amanda G. Jarvis*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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Abstract

A rationally designed dual‐purpose non‐canonical amino acid (Trz) has been synthesised and successfully incorporated into a protein scaffold by genetic code expansion. Trz contains a 5‐pyridyl‐1,2,4‐triazine system, which allows for inverse‐electron‐demand Diels–Alder (IEDDA) reactions to occur on the triazine ring and for metal ions to be chelated both before and after the click reaction. Trz was successfully incorporated into a protein scaffold and the IEDDA utility of Trz demonstrated through the site‐specific labelling of the purified protein with a bicyclononyne. Additionally, Trz was shown to successfully coordinate a cyclometallated iridium(III) centre, providing access to a bioorthogonal luminogenic probe. The luminescent properties of the Ir(III)‐bound protein blue‐shift upon IEDDA click reaction with bicyclononyne, providing a unique method for monitoring the extent and location of the labelling reaction. In summary, Trz is a new dual‐purpose non‐canonical amino acid with great potential for myriad bioapplications where metal‐based functionality is required, for example in imaging, catalysis, and photo‐dynamic therapy, in conjunction with a bioorthogonal reactive handle to impart additional functionalities, such as dual‐modality imaging or therapeutic payloads.
Original languageEnglish
Article numbere202413073
Number of pages5
JournalAngewandte Chemie
Volume136
Issue number52
Early online date13 Sept 2024
DOIs
Publication statusPublished - 20 Dec 2024

Keywords

  • genetic code expansion
  • non-canonical amino acids
  • iridium
  • bioorthogonal reactivity
  • luminescent probes

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