Dual Stimuli-Responsive Dynamic Covalent Peptide Tags: Toward Sequence-Controlled Release in Tumor-like Microenvironments

Dynamic covalent
chemistry (DCvC) has emerged as a versatile synthetic
tool for devising stable, stimuli-responsive linkers or conjugates.
The interplay of binding affinity, association and dissociation constants
exhibits a strong influence on the selectivity of the reaction, the
conversion rate, as well as the stability in aqueous solutions. Nevertheless,
dynamic covalent interactions often exhibit fast binding and fast
dissociation events or vice versa, affecting their conversion rates
or stabilities. To overcome the limitation in linker design, we reported
herein dual responsive dynamic covalent peptide tags combining a pH
responsive boronate ester with fast association and dissociation rates,
and a redox-active disulfide with slow formation and dissociation
rate. Precoordination by boronic acid–catechol interaction
improves self-sorting and selectivity in disulfide formation into
heterodimers. The resulting bis-peptide conjugate exhibited improved
complex stability in aqueous solution and acidic tumor-like extracellular
microenvironment. Furthermore, the conjugate responds to pH changes
within the physiological range as well as to redox conditions found
inside cancer cells. Such tags hold great promise, through cooperative
effects, for controlling the stability of bioconjugates under dilution
in aqueous media, as well as designing intelligent pharmaceutics that
react to distinct biological stimuli in cells.