Issue 34, 2024

Harnessing a bis-electrophilic boronic acid lynchpin for azaborolo thiazolidine (ABT) grafting in cyclic peptides

Abstract

Chemical modifications of native peptides have significantly advanced modern drug discovery in recent decades. On this front, the installation of multitasking molecular grafts onto macrocyclic peptides offers numerous opportunities in biomedical applications. Here, we showcase a new class of borono-cyclic peptides featuring an azaborolo thiazolidine (ABT) graft, which can be readily assembled utilizing a bis-electrophilic boronic acid lynchpin while harnessing the inherent reactivity difference (>103 M−1 s−1) between the N-terminal cysteine and backbone cysteine for rapid and highly regioselective macrocyclization (∼1 h) under physiological conditions. The ABT-crosslinked peptides are fairly stable in endogenous environments, but can provide the linear diazaborine peptides via treatment with α-nucleophiles. This efficient peptide crosslinking protocol was further extended for regioselective bicyclizations and engineering of α-helical structures. Finally, ABT-grafted peptides were exploited in biorthogonal conjugation, leading to highly effective intracellular delivery of an apoptotic peptide (KLA) in cancer cells. The mechanism of action by which ABT-grafted KLA peptide induces apoptosis was also explored.

Graphical abstract: Harnessing a bis-electrophilic boronic acid lynchpin for azaborolo thiazolidine (ABT) grafting in cyclic peptides

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Article information

Article type
Edge Article
Submitted
01 jul 2024
Accepted
24 jul 2024
First published
30 jul 2024
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY-NC license

Chem. Sci., 2024,15, 13688-13698

Harnessing a bis-electrophilic boronic acid lynchpin for azaborolo thiazolidine (ABT) grafting in cyclic peptides

B. K. Das, A. Chowdhury, S. Chatterjee, N. M. Tripathi, B. Pati, S. Dutta and A. Bandyopadhyay, Chem. Sci., 2024, 15, 13688 DOI: 10.1039/D4SC04348K

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