Petri YD,
Gutierrez CS,
Raines RT.
*
Massachusetts Institute of Technology, Cambridge, USA
Chemoselective Caging of Carboxyl Groups for On-Demand Protein Activation with Small
Molecules.
Angew. Chem. Int. Ed. 2023;
62: e202215614
DOI:
10.1002/anie.202215614
Key words
cage - 1,3-dipolar cycloaddition - Staudinger reduction
Significance
Amino acid cages are valuable chemical tools for controlling the activity and interactions
of proteins. Protein cages have been primarily designed for Lys, Tyr, and Sec amino
acids. In this study, the authors expand this toolbox by developing diazo-based compound
1 that can selectively cage solvent-exposed amino acids containing carboxyl groups.
The caged residues can be released, in a traceless fashion, with two small-molecule
triggers.
Comment
To demonstrate the utility of their tool, the authors caged lysozyme (Lyz), which
has a catalytic Glu35 with elevated pK
a. Lyz-1 shows severely reduced catalytic activity, which can be recovered through the addition
of commercially available 2-DPBA and TCO-OH. The addition of these two small-molecule
triggers leads to uncaging to the wild-type Lyz enzyme.
