Chemical diversification of polyprenyl quinones for mechanistic studies on menaquinone-binding peptide antibiotics

Abstract

Polyprenyl quinones, such as ubiquinone and menaquinone, are essential membrane-embedded redox cofactors that are involved in electron transport and found across all domains of life. However, their highly hydrophobic structure, which includes a quinone head-group and long polyprenyl tail, has limited their chemical derivatization for biological studies. Here, we report a versatile synthetic approach for the chemical diversification of natural polyprenyl quinones, enabling the introduction of various reporter groups including fluorophores, quenchers, NMR-active nuclei, and photoaffinity and bioaffinity tags. These functionalized analogues retain their membrane-associating properties and enable new applications in antibiotic discovery. We show that fluorescently labelled menaquinone analogues retain their strong binding affinity to the menaquinone-binding peptide antibiotics lysocin E and lysomeb (MBA2). Incorporation of BODIPY–quinones into vesicles allowed visualization of the peptide–quinone interaction, revealing their effects on membrane integrity and quinone aggregation. This study expands the chemical toolbox for polyprenyl quinones, enabling targeted functionalization of these essential biomolecules and facilitating further exploration of their roles in biological systems.

Graphical abstract: Chemical diversification of polyprenyl quinones for mechanistic studies on menaquinone-binding peptide antibiotics

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Article information

Article type
Edge Article
Submitted
09 May 2025
Accepted
02 Jul 2025
First published
03 Jul 2025
This article is Open Access

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

Chem. Sci., 2025, Advance Article

Chemical diversification of polyprenyl quinones for mechanistic studies on menaquinone-binding peptide antibiotics

E. J. Matheson, R. A. M. van Beekveld, P. Innocenti, N. I. Martin, M. Weingarth and S. A. Cochrane, Chem. Sci., 2025, Advance Article , DOI: 10.1039/D5SC03363B

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