Structural Analysis and Activity Correlation of Amphiphilic Cyclic Antimicrobial Peptides Derived from the [WR] Scaffold

Overview

Journal Molecules

Publisher MDPI

Specialty Biology

Date 2023 Dec 23

PMID 38138539

Authors

Shaima A El-Mowafi

Anastasia G Konshina

Eman H M Mohammed

Nikolay A Krylov

Roman G Efremov

Keykavous Parang

Affiliations

Soon will be listed here.

Abstract

In our ongoing quest to design effective antimicrobial peptides (AMPs), this study aimed to elucidate the mechanisms governing cyclic amphiphilic AMPs and their interactions with membranes. The objective was to discern the nature of these interactions and understand how peptide sequence and structure influence antimicrobial activity. We introduced modifications into the established cyclic AMP peptide, [WR], incorporating an extra aromatic hydrophobic residue (W), a positively charged residue (R), or the unique 2,5-diketopiperazine (DKP). This study systematically explored the structure-activity relationships (SARs) of a series of cyclic peptides derived from the [WR] scaffold, including the first synthesis and evaluation of [WR(DKP)]. Structural, dynamic, hydrophobic, and membrane-binding properties of four cyclic peptides ([WR], [WR], [WR], [WR(DKP)]) were explored using molecular dynamics simulations within a DOPC/DOPG lipid bilayer that mimics the bacterial membrane. The results revealed distinct SARs linking antimicrobial activity to parameters such as conformational plasticity, immersion depth in the bilayer, and population of the membrane binding mode. Notably, [WR] exhibited an optimal "activity/binding to the bacterial membrane" pattern. This multidisciplinary approach efficiently decoded finely regulated SAR profiles, laying a foundation for the rational design of novel antimicrobial peptides.

Citing Articles

Antibacterial and Antifungal Activities of Linear and Cyclic Peptides Containing Arginine, Tryptophan, and Diphenylalanine.

Salehi D, Mohammed E, Helmy N, Parang K Antibiotics (Basel). 2025; 14(1).

PMID: 39858368 PMC: 11763264. DOI: 10.3390/antibiotics14010082.

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