Poster Presentation 10th Modern Solid Phase Peptide Synthesis & Its Applications Symposium 2025

Developing an Aza-Michael Route to Quaternary Ammonium Compounds and its Application to Antimicrobials (129124)

Rolland Lin 1 2 3 , Margaret A Brimble 1 2 3 , Brian H Northrop 4 , Alan J Cameron 1 2 3
  1. School of Chemical Sciences, The University of Auckland, Auckland, New Zealand
  2. Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Auckland, New Zealand
  3. School of Biological Sciences, The University of Auckland, Auckland, New Zealand
  4. Chemistry, Wesleyan University, Middletown, Connecticut, USA

With the growing prominence of peptide therapeutics, expanding the peptide chemistry toolbox is valuable for opening new avenues to enhance their properties or introduce novel functionalities. One such functionality is the quaternary ammonium moiety, a positively charged nitrogen group widely utilised for its antimicrobial properties.1,2

We present a facile and chemoselective aza-Michael addition reaction to chemically modify peptides with the quaternary ammonium moiety as a late-stage modification. This ‘click’ reaction employs readily available reagents and eliminates the requirement for toxic alkylating reagents traditionally used in the synthesis of quaternary ammonium compounds. Using this chemistry, peptide bond containing vinyl quaternary ammonium analogues of commercially available disinfectants such as benzalkonium chloride (BAC) were prepared. The resulting compounds demonstrated superior anti-biofilm activity and dramatically reduced toxicity to airway tissues in an ex vivo assay utilising patient derived samples. Application of this strategy to an antimicrobial lipopeptide scaffold (polymyxin B) through Fmoc-SPPS resulted in a broadened spectrum of antimicrobial activity. We envision broader application of this strategy in the fields of peptide science and chemical biology such as aiding peptide solubility, peptide stapling, use as a temporary protecting group for a Michael acceptor and facilitating detection of N-dimethylated peptides/proteins for mass spectrometry-based proteomics by exploiting the quaternary ammonium group’s permanent charge.

 

(1)        Ongwae, G. M.; Morrison, K. R.; Allen, R. A.; Kim, S.; Im, W.; Wuest, W. M.; Pires, M. M. Broadening Activity of Polymyxin by Quaternary Ammonium Grafting. ACS Infect. Dis. 2020, 6 (6), 1427–1435. https://doi.org/10.1021/acsinfecdis.0c00037.

(2)        Okano, A.; Isley, N. A.; Boger, D. L. Peripheral Modifications of [Ψ[CH2NH]Tpg4]Vancomycin with Added Synergistic Mechanisms of Action Provide Durable and Potent Antibiotics. Proc. Natl. Acad. Sci. U.S.A. 2017, 114 (26), E5052–E5061. https://doi.org/10.1073/pnas.1704125114.