The complex social ecosystem regulates the spectrum of
human behavior.
However, it becomes relatively easier to understand if we disintegrate
the contributing factors, such as locality and interacting partners.
Interestingly, it draws remarkable similarity with the behavior of
a residue placed in a social setup of functional groups in a protein.
Can it inspire principles for creating a unique environment for the
precision engineering of proteins? We demonstrate that localization-regulated
interacting partner(s) could render precise and traceless single-site
modification of structurally diverse native proteins. The method targets
a combination of high-frequency Lys residues through an array of reversible
and irreversible reactions. However, excellent simultaneous control
over chemoselectivity, site selectivity, and modularity ensures that
the user-friendly protocol renders acyl group installation, including
post-translational modifications (PTMs), on a single Lys. Besides,
it offers a chemically orthogonal handle for the installation of probes.
Also, a purification protocol integration delivers analytically pure
single-site tagged protein bioconjugates. The precise labeling of
a surface Lys residue ensures that the structure and enzymatic activities
remain conserved post-bioconjugation. For example, the precise modification
of insulin does not affect its uptake and downstream signaling pathway.
Further, the method enables the synthesis of homogeneous antibody–fluorophore
and antibody–drug conjugates (AFC and ADC; K183 and K249 labeling).
The trastuzumab–rhodamine B conjugate displays excellent serum
stability along with antigen-specific cellular imaging. Further, the
trastuzumab–emtansine conjugate offers highly specific antiproliferative
activity toward HER-2 positive SKBR-3 breast cancer cells. This work
validates that disintegrate theory can create a comprehensive platform
to enrich the chemical toolbox to meet the technological demands at
the chemistry, biology, and medicine interface.
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