Open AccessDual Stimuli-Responsive Dynamic Covalent Peptide Tags: Toward Sequence-Controlled Release in Tumor-like Microenvironments
Author(s) -
Maksymilian Marek Zegota,
Michael Müller,
Bellinda Lantzberg,
Gönül Kızılsavaş,
Jaime A. S. Coelho,
Pierpaolo Moscariello,
María Martínez-Negro,
Svenja Morsbach,
Pedro M. P. Góis,
Manfred Wagner,
David Y. W. Ng,
Seah Ling Kuan,
Tanja Weil
Publication year - 2021
Publication title -
journal of the american chemical society
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.115
H-Index - 612
eISSN - 1520-5126
pISSN - 0002-7863
DOI - 10.1021/jacs.1c06559
Subject(s) - chemistry , covalent bond , conjugate , dissociation (chemistry) , combinatorial chemistry , redox , peptide , aqueous solution , dynamic covalent chemistry , selectivity , biophysics , linker , biochemistry , organic chemistry , molecule , catalysis , supramolecular chemistry , mathematical analysis , mathematics , biology , computer science , operating system
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.