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. 2021;32(14):1371-1378.
doi: 10.1055/a-1479-6366. Epub 2021 Apr 11.

Targeting Tryptophan for Tagging Through Photo-induced Electron Transfer

Norberto V Orellana  1 , Michael T Taylor  1
Affiliations

Targeting Tryptophan for Tagging Through Photo-induced Electron Transfer

Norberto V Orellana et al. Synlett. 2021.

Abstract

The chemical modification of tryptophan (Trp) has been the subject of interest for nearly 100 years, yet the development modification conditions that exploit Trp's inherent photolability have remained elusive. In this perspective, we discuss our recently reported method for Tryptophan (Trp) photobioconjugation that uses N -carbamoyl pyridinium salts to engage Trp in photo-induced electron transfer. We detail our inspiration and rationale as well as place our report in the context of select prior art in the field.

Keywords: Bioconjugation; Photo-induced Electron Transfer; Photochemistry; Proteins; Tryptophan.

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Figures

Scheme 1
Scheme 1
(A) An idealized bioconjugation scenario. (B) An idealized photo-bioconjugation scenario.
Scheme 2
Scheme 2
Prior Art. (A) Selected examples of photochemical manipulation of Trp and Trp-containing proteins. (B) Selected examples of thermal chemistries for chemoselective Trp modification.
Scheme 3
Scheme 3
(A) Select photophysical and photochemical reactivity profiles of Trp. (B) Reactivity profile of activated N-substituted pyridinium salts. (C) Merging the photochemistries of N-substituted pyridinium salts with that of Trp to develop a chemoselective photobioconjugation strategy. FAD=Flavin Adenine dinucleotide
Scheme 4
Scheme 4
(A) Optimized conditions for the labelling of Octreotide (2). (B) Transferring group scope of 1. (C) A modular synthetic route to bespoke 1 derivatives. Conversions were estimated via LC-MS.
Scheme 5
Scheme 5
Peptide and protein Labelling scope using 1a. aperformed using Tris(2-carboxyethyl)phosphine (TCEP) (1 mM) as an additive. Conversions were estimated by LC-MS.
Scheme 6
Scheme 6
Proposed mechanism of labelling of Trp with 1a.
Scheme 7
Scheme 7
(A) Labelling of lysozyme, a photolabile protein, with 1a. (B) Design of pyridinium salt 1d, which possesses a bathochromically shifted absorption spectrum compared to 1a. (C) Reversal of the mechanism of the labelling process from [Trp]*→1 to Trp→[1]* affords a superior labelling process that circumvents protein photolability. Conversions were estimated by LC/MS.
See this image and copyright information in PMC

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