TY - JOUR
T1 - A Dual-Purpose Non‐Canonical Amino Acid for the Expanded Genetic Code
T2 - Combining Metal‐Binding and Click Chemistry
AU - Day, Graham J.
AU - Zaytsev, Andrey V.
AU - Brewster, Richard C.
AU - Kozhevnikov, Valery N.
AU - Jarvis, Amanda G.
PY - 2024/12/20
Y1 - 2024/12/20
N2 - 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.
AB - 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.
KW - genetic code expansion
KW - non-canonical amino acids
KW - iridium
KW - bioorthogonal reactivity
KW - luminescent probes
UR - http://www.scopus.com/inward/record.url?scp=85207570021&partnerID=8YFLogxK
U2 - 10.1002/ange.202413073
DO - 10.1002/ange.202413073
M3 - Article
SN - 0044-8249
VL - 136
JO - Angewandte Chemie
JF - Angewandte Chemie
IS - 52
M1 - e202413073
ER -