Dynamic covalent chemistry enables formation of antimicrobial peptide quaternary assemblies in a completely abiotic manner

Abstract

Naturally occurring peptides and proteins often use dynamic disulfide bonds to impart defined tertiary/quaternary structures for the formation of binding pockets with uniform size and function. Although peptide synthesis and modification are well established, controlling quaternary structure formation remains a significant challenge. Here, we report the facile incorporation of aryl aldehyde and acyl hydrazide functionalities into peptide oligomers via solid-phase copper-catalysed azide-alkyne cycloaddition (SP-CuAAC) click reactions. When mixed, these complementary functional groups rapidly react in aqueous media at neutral pH to form peptide-peptide intermolecular macrocycles with highly tunable ring sizes. Moreover, sequence-specific figure-of-eight, dumbbell-shaped, zipper-like and multi-loop quaternary structures were formed selectively. Controlling the proportions of reacting peptides with mismatched numbers of complementary reactive groups results in the formation of higher-molecular-weight sequence-defined ladder polymers. This also amplified antimicrobial effectiveness in select cases. This strategy represents a general approach to the creation of complex abiotic peptide quaternary structures.

Light‐Activated Rapid Disinfection by Accelerated Charge Transfer in Red Phosphorus/ZnO Heterointerface

“…Pathogenic microorganisms related to infectious diseases are the second largest murderer of death worldwide with 17 million annual victims . There is an increasing demand to explore innovative disinfection techniques in response to the prevalence of pathogenic microorganisms and bacterial outbreaks originating from medical treatment, contaminated water reservoirs, human contact, and so on . Specifically, medical device‐associated infections contribute to a great part of hospital‐acquired infections, which make up 25.6% of all health‐care‐associated infections in the USA .…”

Self-triggered click reaction in an Alzheimer's disease model:in situbifunctional drug synthesis catalyzed by neurotoxic copper accumulated in amyloid-β plaques

“…3 It is a promising strategy to harness toxic Cu under pathological conditions for defense against disease rather than just to chelate Cu. [4][5][6] Due to its high efficiency, fast kinetics, and mild reaction conditions, the Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction has received special attention in many biochemical applications such as bioconjugation, [7][8][9][10][11] biosensing, [12][13][14] and drug synthesis. 15,16 Many kinds of Cu sources are efficient for CuAAC bioorthogonal reactions.…”

A Versatile Approach to Noncanonical, Dynamic Covalent Single- and Multi-Loop Peptide Macrocycles for Enhancing Antimicrobial Activity

“…26 Very recently, our group reported the facile incorporation of aldehyde and hydrazide functionalities using solid-phase copper-catalyzed azide–alkyne cycloaddition (SP-CuAAC) “click” reactions (Scheme 1). 27 Alkyne derivatives of these functionalities are “clicked” onto azidolysine (AzK) amino acid residues incorporated via solid-phase peptide synthesis (SPPS).…”