Double Orthogonal Click Reactions for the Development of Antimicrobial Peptide Nanotubes

Abstract

A new class of amphipathic cyclic peptides, which assemble in bacteria membranes to form polymeric supramolecular nanotubes giving them antimicrobial properties, is described. The method is based on the use of two orthogonal clickable transformations to incorporate different hydrophobic or hydrophilic moieties in a simple, regioselective, and divergent manner. The resulting cationic amphipathic cyclic peptides described in this article exhibit strong antimicrobial properties with a broad therapeutic window. Our studies suggest that the active form is the nanotube resulted from the parallel stacking of the cyclic peptide precursors. Several techniques, CD, FTIR, fluorescence, and STEM, among others, confirm the nanotube formation.

1D alignment of proteins and other nanoparticles by using reversible covalent bonds on cyclic peptide nanotubes

“…These hybrid biomaterials and this methodology could find applications in novel culture cell techniques, in catalysis, molecular storage, and drug delivery, among others. 2,13,25…”

“…This provides an association constant larger than any other previously reported CPs. 5,9,10,13 This can be related to the additional formation of two hydrogen bonds between the glutaric acid spacers (see model in Scheme 2).…”

“…12 Recently, click chemistry transformations have been used to incorporate not only polymers, but also alkyl chains to provide antimicrobial activity based on their membrane disrupting properties. 13 In the last years, we have used a pyrene moiety attached to CPs, not only as a molecular probe to follow the assembling process, but also to supramolecularly interact with other molecules, such as single wall carbon nanotubes or small silver clusters in the fabrication of new hybrid materials (Fig. 1).…”

Heteroglycoclusters through Unprecedented Orthogonal Chemistry Based on N‐Alkylation of N‐Acylhydrazone

“…[20][21][22] Although it remains a challenging problem to overcome, this orthogonal strategy based on sequential chemo-selective reactions remains an approach [23] that provides a relevant solution to design complex molecules for a wide range of applications. [23][24][25] It is particularly appropriate in the context of biologically active molecules as heteroglycolcusters. [7,26,27] N-acylhydrazone (NAH) is a popular function that enjoys significant attention in organic and biomaterial chemistries thanks to its dynamic covalent bond [28] and its use as an intermediate in miscellaneous reactions.…”

“…The third uses suitably orthogonally functionalized scaffolds sequentially crosslinked to various sugars in a controlled manner [20–22] . Although it remains a challenging problem to overcome, this orthogonal strategy based on sequential chemo‐selective reactions remains an approach [23] that provides a relevant solution to design complex molecules for a wide range of applications [23–25] . It is particularly appropriate in the context of biologically active molecules as heteroglycolcusters [7,26,27] .…”