Covalent Affibody-Molecular Glue Drug Conjugate Nanoagent for Proximity-Enabled Reactive Therapeutics.

ABSTRACT: Sulfur-fluoride exchange (SuFEx) reaction is an emerging class of click chemistry reaction. Owing to its efficient reactivity under physiological conditions, SuFEx reaction is used to construct covalent protein drugs. Herein, a covalent affibody-molecular glue drug conjugate nanoagent is reported, which can irreversibly bind with its target protein through proximity-enabled SuFEx reaction. As a proof of concept, a latent bioreactive unnatural amino acid fluorosulfate-L-tyrosine (FSY) is first introduced at site 36 of the affibody with cysteine mutation (Z_HER2:342-Cys) to produce Z_HER2:342-36_FSY-Cys. Subsequently, Z_HER2:342-36_FSY-Cys is coupled with a molecular glue drug (CR8) to yield an amphiphilic conjugate of Z_HER2:342-36

SUBMITTER: Gao W 

PROVIDER: S-EPMC11905048 | biostudies-literature | 2025 Mar

REPOSITORIES: biostudies-literature