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Biomolecules 2018, 8(2), 19; https://doi.org/10.3390/biom8020019

Improving the Activity of Trp-Rich Antimicrobial Peptides by Arg/Lys Substitutions and Changing the Length of Cationic Residues

1
Biochemistry Research Group, Department of Biological Sciences, University of Calgary, Calgary, AB T2N 1N4, Canada
2
Physics School, Faculty of Science, Universidad Nacional de Colombia, Medellín, Antioquia 050034, Colombia
3
Department of Surgery, Division of Urology, Southern Alberta Institute of Urology, University of Calgary, Calgary, AB T2V 1P9, Canada
*
Author to whom correspondence should be addressed.
Received: 10 March 2018 / Revised: 14 April 2018 / Accepted: 17 April 2018 / Published: 19 April 2018
(This article belongs to the Special Issue Antimicrobial Peptides: Development, Conjugation, and Beyond)
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Abstract

Antimicrobial peptides (AMPs) constitute a promising alternative for the development of new antibiotics that could potentially counteract the growing number of antibiotic-resistant bacteria. However, the AMP structure–function relationships remain unclear and detailed studies are still necessary. The positively charged amino acid residues (Arg and Lys) play a crucial role in the activity of most AMPs due to the promotion of electrostatic interactions between the peptides and bacterial membranes. In this work we have analyzed the antimicrobial and structural properties of several Trp-rich AMPs containing exclusively either Arg or Lys as the positively charged residues. Their antimicrobial activity and mechanism of action were investigated, showing that Lys residues give rise to a reduced antimicrobial potency for most peptides, which was correlated, in turn, with a decrease in their ability to permeabilize the cytoplasmic membrane of Escherichia coli. Additionally, the presence of Arg and Lys renders the peptides susceptible to degradation by proteases, such as trypsin, limiting their therapeutic use. Therefore, modifications of the side chain length of Arg and Lys were investigated in an attempt to improve the protease resistance of AMPs. This approach resulted in enhanced stability to trypsin digestion, and in several cases, shorter sidechains conserved or even improved the antimicrobial activity. All together, these results suggest that Arg-to-Lys substitutions, coupled with side chain length modifications, can be extremely useful for improving the activity and stability of AMPs. View Full-Text
Keywords: antimicrobial peptides; tritrpticin; arginine; lysine; protease degradation; trypsin antimicrobial peptides; tritrpticin; arginine; lysine; protease degradation; trypsin
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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. (CC BY 4.0).
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Arias, M.; Piga, K.B.; Hyndman, M.E.; Vogel, H.J. Improving the Activity of Trp-Rich Antimicrobial Peptides by Arg/Lys Substitutions and Changing the Length of Cationic Residues. Biomolecules 2018, 8, 19.

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