Backbone Cyclization and Dimerization of LL-37-Derived Peptides Enhance Antimicrobial Activity and Proteolytic Stability

Frontiers in Microbiology
Sunithi GunasekeraUlf Göransson

Abstract

Can antimicrobial activity and peptide stability of alpha-helical peptides be increased by making them into dimers and macrocycles? Here, we explore that concept by using KR-12 as the starting point for peptide engineering. KR-12 has previously been determined as the minimalized antimicrobial fragment of the human host defense peptide LL-37. Backbone-cyclized KR-12 dimers, tethered by linkers of two to four amino acid residues, were synthesized and their antimicrobial activity, proteolytic stability and structures characterized. A modified KR-12 sequence, with substitutions at previously identified key residues, were also included in the screening panel. The backbone cyclized KR-12 dimers showed improved antimicrobial activity and increased stability compared to monomeric KR-12. The most active cyclic dimer displayed 16-fold higher antibacterial activity compared to KR-12 against Pseudomonas aeruginosa and Staphylococcus aureus, and 8-fold increased fungicidal activity against Candida albicans. It also showed increased hemolytic and cytotoxic activity. Enhanced antimicrobial activity coincided with increased membrane permeabilization of liposomes with one distinct discrepancy: monomeric KR-12 was much less disruptive of liposom...Continue Reading

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Citations

Sep 3, 2020·American Journal of Physiology. Lung Cellular and Molecular Physiology·Kent A WillisNamasivayam Ambalavanan
Dec 1, 2020·PloS One·Nathaniel NelsonDaniel K Schwartz
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Oct 16, 2021·Journal of Agricultural and Food Chemistry·Shuhui ZhangAimin Ma

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Methods Mentioned

BETA
NMR
circular dichroism
size exclusion chromatography
Assay

Software Mentioned

CYANA
XEASY
CARA
MOLMOL
PYMOL
MolProbity
Topspin
TALOS
PyMOL ( Molecular Graphics System
GraphPad Prism

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