Dual stimuli-responsive dynamic covalent peptide tags: Towards sequence-controlled release in tumor-like microenvironments

Abstract

Dynamic covalent chemistry (DCvC) has emerged as a versatile synthetic tool for devising stable, stimuli-responsive bioconjugates. 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 in combination with fast dissociation events and vice versa. To overcome the intrinsic limitation, we have designed dynamic covalent peptide tags combining two different pairs of dynamic covalent interactions with different reaction kinetics:(1) the fast association of boronic acid and catechol that forms pH-sensitive and rapidly dissociating boronate esters, and (2) the slower formation of a redox-active disulfide bond with slow dissociation rate. Pre-coordination of the thiols of the cysteine residues by the fast boronic acid-catechol interaction primarily yields the heterodimers proving selectivity and self-sorting capability of the reaction, with improved complex stability in aqueous solution and even in the acidic tumor-like extracellular microenvironment. The resulting bis-peptide conjugate responds to pH changes within the physiological range as well as to a redox environment that is similar to certain conditions found inside cancer cells. We believe that 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 cellular environments.

Trialkoxysilane Exchange: Scope, Mechanism, Cryptates and pH‐Response

“…Dynamic covalent chemistry (DCvC) as a research field that seeks to study and utilize reversible covalent bonds has been enabling advances in, e.g., bioconjugation, [1][2][3][4][5][6][7][8][9] supramolecular chemistry [10][11][12][13][14][15][16][17][18][19][20][21] and organic materials. [22][23][24][25][26][27][28][29][30][31][32][33][34][35] Over the last two decades, the DCvC toolbox has been systematically extended from imines, olefins, thioesters, disulfides, hydrazones and boronic esters, [36,37] to diselenides, [38,39] tetrazines, [40,41] triazines, [42,43] (hemi)aminals, [44,45] dithioacetals, [46,47] orthoesters, [48,…”