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

James F. Reuther, Andrew C. Goodrich, P. Rogelio Escamilla, Tiffany A. Lu, Valarie Del Rio, Bryan W. Davies*, Eric V. Anslyn

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

10 Citations (Scopus)

Abstract

Peptide oligomers offer versatile scaffolds for the formation of potent antimicrobial agents due to their high sequence versatility, inherent biocompatibility, and chemical tunability. Though many methods exist for the formation of peptide-based macrocycles (MCs), increasingly pervasive in commercial antimicrobial therapeutics, the introduction of multiple looped structures into a single peptide oligomer remains a significant challenge. Herein, we report the utilization of dynamic hydrazone condensation for the versatile formation of single-, double-, and triple-loop peptide MCs using simple dialdehyde or dihydrazide small-molecule cross-linkers, as confirmed by MALDI-TOF MS, HPLC, and SDS-PAGE. Furthermore, incorporation of aldehyde-containing side chains onto peptides synthesized from hydrazide C-terminal resins resulted in tunable peptide MC assemblies formed directly upon resin cleavage post solid-phase peptide synthesis. Both of these types of dynamic covalent assemblies produced significant enhancements to overall antimicrobial properties when introduced into a known antimicrobial peptide, buforin II, when compared to the original unassembled sequence.

Original languageEnglish
Pages (from-to)3768-3774
Number of pages7
JournalJournal of the American Chemical Society
Volume140
Issue number10
Early online date21 Feb 2018
DOIs
Publication statusPublished - 14 Mar 2018
Externally publishedYes

Bibliographical note

Funding Information:
The presented work was supported financially under the DAPRA Fold-Fx program (N66001-14-2-4051), NIH (AI25337), and the Welch Regents Chair (F-0046 and F-1870). We would also like to thank Maria Persons of the University of Texas at Austin Proteomics Facility and Ian Riddington of the Mass Spectrometry Facility at UT Austin for their aid in MALDI-TOF MS and HRMS acquisition.

Publisher Copyright:
© 2018 American Chemical Society.

Copyright:
Copyright 2018 Elsevier B.V., All rights reserved.

ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)
  • Biochemistry
  • Colloid and Surface Chemistry

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