Universität zu Köln

Quagliata, Michael ORCID: 0000-0003-0891-3405, Grabeck, Joshua ORCID: 0000-0003-1126-1647, König, Kathrin, Papini, Anna Maria ORCID: 0000-0002-2947-7107, Rovero, Paolo ORCID: 0000-0001-9577-5228, Neundorf, Ines ORCID: 0000-0001-6450-3991 and Friedrich, Daniel ORCID: 0009-0006-4393-5692 (2025). α-Helical Structure of Antimicrobial Peptides Enhances Their Activity through Molecular Surface Signatures. Biochemistry, 64 (15). pp. 3311-3321. American Chemical Society (ACS). ISSN 0006-2960

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Abstract

The increase in antibacterial resistance is one of the greatest challenges in modern medicine, driving an urgent need to develop new drugs to combat resistant pathogens. Peptides represent a promising class of molecules that can be efficiently designed to exhibit high antimicrobial efficacy. Recently, we have highlighted how prestructuring by a triazolyl-bridge significantly enhances the activity of an antimicrobial peptide. To learn more from these findings, the aim of this study is to relate the NMR-based structure of a triazolyl-bridged peptide to its antimicrobial activity against Gram-positive and Gram-negative bacteria in comparison to its linear analogues. As we show, the triazole modification indeed induces a well-defined α-helical structure, resulting in an improved positive electrostatic surface potential on one side of the peptide and clustering of hydrophilic and hydrophobic residues on opposite surface areas of the molecule. Systematic alanine substitution further suggested that the side chains of arginine 3 and 7 and of asparagine 11 have a stronger productive impact on antimicrobial activity than those of lysine 4, 8, and 12. As shown by micelle-bound peptide structures determined by NMR, we identify arginine 3 and asparagine 11 as presumable membrane-interacting residues. Collectively, our NMR-based analysis provides evidence that an α-helical structure enhances antimicrobial activity by creating positively charged and hydrophilic, and hydrophobic areas as molecular surface signatures, potentially promoting the interaction of the peptide with the cellular target membrane.

Item Type:	Article
Creators:	Creators Email ORCID ORCID Put Code Quagliata, Michael UNSPECIFIED https://orcid.org/0000-0003-0891-3405 UNSPECIFIED Grabeck, Joshua UNSPECIFIED https://orcid.org/0000-0003-1126-1647 UNSPECIFIED König, Kathrin UNSPECIFIED UNSPECIFIED UNSPECIFIED Papini, Anna Maria UNSPECIFIED https://orcid.org/0000-0002-2947-7107 UNSPECIFIED Rovero, Paolo UNSPECIFIED https://orcid.org/0000-0001-9577-5228 UNSPECIFIED Neundorf, Ines UNSPECIFIED https://orcid.org/0000-0001-6450-3991 UNSPECIFIED Friedrich, Daniel UNSPECIFIED https://orcid.org/0009-0006-4393-5692 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-798466
Identification Number:	10.1021/acs.biochem.5c00101
Journal or Publication Title:	Biochemistry
Volume:	64
Number:	15
Page Range:	pp. 3311-3321
Number of Pages:	11
Date:	5 August 2025
Publisher:	American Chemical Society (ACS)
ISSN:	0006-2960
Language:	English
Faculty:	Faculty of Mathematics and Natural Sciences
Divisions:	Faculty of Mathematics and Natural Sciences > Department of Chemistry > Institute of Biochemistry
Subjects:	Chemistry and allied sciences Life sciences
['eprint_fieldname_oa_funders' not defined]:	Publikationsfonds UzK
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/79846