El-Mowafi, S.A.; Konshina, A.G.; Mohammed, E.H.M.; Krylov, N.A.; Efremov, R.G.; Parang, K. Structural Analysis and Activity Correlation of Amphiphilic Cyclic Antimicrobial Peptides Derived from the [W4R4] Scaffold. Molecules2023, 28, 8049.
El-Mowafi, S.A.; Konshina, A.G.; Mohammed, E.H.M.; Krylov, N.A.; Efremov, R.G.; Parang, K. Structural Analysis and Activity Correlation of Amphiphilic Cyclic Antimicrobial Peptides Derived from the [W4R4] Scaffold. Molecules 2023, 28, 8049.
El-Mowafi, S.A.; Konshina, A.G.; Mohammed, E.H.M.; Krylov, N.A.; Efremov, R.G.; Parang, K. Structural Analysis and Activity Correlation of Amphiphilic Cyclic Antimicrobial Peptides Derived from the [W4R4] Scaffold. Molecules2023, 28, 8049.
El-Mowafi, S.A.; Konshina, A.G.; Mohammed, E.H.M.; Krylov, N.A.; Efremov, R.G.; Parang, K. Structural Analysis and Activity Correlation of Amphiphilic Cyclic Antimicrobial Peptides Derived from the [W4R4] Scaffold. Molecules 2023, 28, 8049.
Abstract
In our previous work, we demonstrated the potential of the amphiphilic cyclic peptide [W4R4] as a promising antimicrobial agent. The extensive data accumulated on the antimicrobial activity of this peptide and its homologs presented an opportunity to unravel the molecular mechanisms governing their action and establish crucial structure-activity relationships (SAR). To achieve this, we employed a comprehensive approach involving peptide synthesis, in vitro biological testing, and molecular modeling to systematically analyze the SAR of a series of cyclic peptides derived from the [W4R4] scaffold. Minimal modifications were introduced to the original peptide by incorporating either one aromatic hydrophobic residue (W) or one polar positively charged residue (R) while maintaining the sequential W/R arrangement. Additionally, we introduced an "intermediate" substitution by incorporating 2,5-diketopiperazine (DKP), possessing both aromatic and polar properties, into the macrocycle [W4R4] between the W and R residues. Notably, this study marked the first synthesis and evaluation of the [W4R4(DKP)] peptide. Structural, dynamic, hydrophobic, and membrane-binding properties of four cyclic peptides ([W4R4], [W5R4], [W4R5], [W4R4(DKP)]) were explored using molecular dynamics simulations within a DOPC/DOPG lipid bilayer that mimics the bacterial membrane. The results obtained revealed distinct SAR profiles for all peptides, enabling the establishment of correlations between their antimicrobial activity and structural/dynamic parameters. These parameters included the degree of conformational plasticity, the depth of immersion into the bi-layer, and the population of the membrane binding mode characterized by the embedding of the hydrophobic peptide pattern into the acyl chain region of lipids. In particular, the peptide [W4R5] exhibited an optimal "activity/binding to the bacterial membrane" pattern. This work highlights the significance of our multidisciplinary approach in efficiently deciphering finely regulated SAR profiles for a series of homologous peptides with diverse activities. Furthermore, this research provides a solid foundation for the rational design of novel antimicrobial peptides.
Medicine and Pharmacology, Medicine and Pharmacology
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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