Comparative functional properties of engineered cationic antimicrobial peptides consisting exclusively of tryptophan and either lysine or arginine

Deslouches, Berthony; Hasek, Mary; Craigo, Jodi K.; Steckbeck, Jonathan D.; Montelaro, Ronald C.

doi:10.1099/jmm.0.000258

Cited by 40 publications

(46 citation statements)

References 66 publications

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“…Particularly, it can be used to get information on the kinetics of binding. Different studies have used SPR to study interactions of membrane active peptides with model membranes [ 237 , 238 , 239 , 240 ].…”

Section: Live Imagingmentioning

confidence: 99%

Membrane Active Peptides and Their Biophysical Characterization

2018

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In the last 20 years, an increasing number of studies have been reported on membrane active peptides. These peptides exert their biological activity by interacting with the cell membrane, either to disrupt it and lead to cell lysis or to translocate through it to deliver cargos into the cell and reach their target. Membrane active peptides are attractive alternatives to currently used pharmaceuticals and the number of antimicrobial peptides (AMPs) and peptides designed for drug and gene delivery in the drug pipeline is increasing. Here, we focus on two most prominent classes of membrane active peptides; AMPs and cell-penetrating peptides (CPPs). Antimicrobial peptides are a group of membrane active peptides that disrupt the membrane integrity or inhibit the cellular functions of bacteria, virus, and fungi. Cell penetrating peptides are another group of membrane active peptides that mainly function as cargo-carriers even though they may also show antimicrobial activity. Biophysical techniques shed light on peptide–membrane interactions at higher resolution due to the advances in optics, image processing, and computational resources. Structural investigation of membrane active peptides in the presence of the membrane provides important clues on the effect of the membrane environment on peptide conformations. Live imaging techniques allow examination of peptide action at a single cell or single molecule level. In addition to these experimental biophysical techniques, molecular dynamics simulations provide clues on the peptide–lipid interactions and dynamics of the cell entry process at atomic detail. In this review, we summarize the recent advances in experimental and computational investigation of membrane active peptides with particular emphasis on two amphipathic membrane active peptides, the AMP melittin and the CPP pVEC.

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Section: Live Imagingmentioning

confidence: 99%

Membrane Active Peptides and Their Biophysical Characterization

2018

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“…The positively charged residues (Arg and Lys) have been shown to be extremely important for the activity of the peptides, due to their ability to promote electrostatic attraction with the negatively charged membrane of microorganisms such as bacteria [ 9 , 10 ]. Similarly, bulky hydrophobic residues, including Trp, have been shown to play a key role for most AMPs in the hydrophobic interactions that occur subsequent to the initial electrostatic attraction [ 11 , 12 ]. However, the same residues that are essential for the activity of AMPs also constitute an Achilles’ heel when they are considered for systemic use against infections.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2018

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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.

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“…A study of the antimicrobial peptide amide BP100, KKLFKKILKYL, showed that a single substitution with arginine at lys 9 improved antimicrobial activity without any detectable increase in toxicity [24]. Another study of antimicrobial peptides consisting of exclusively arginine and tryptophan of varying length showed that arginine compared to lysine could yield some antimicrobial peptides with enhanced antimicrobial activity [27]. However, improvements in the antimicrobial activity was not seen for 33-36.…”

Section: Manipulating Cationicity By Lys-arg Substitutions (Compound mentioning

confidence: 99%

Structure-Activity Study of an All-d Antimicrobial Octapeptide D2D

et al. 2019

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The increasing emergence of multi-drug resistant bacteria is a serious threat to public health worldwide. Antimicrobial peptides have attracted attention as potential antibiotics since they are present in all multicellular organisms and act as a first line of defence against invading pathogens. We have previously identified a small all-d antimicrobial octapeptide amide kk(1-nal)fk(1-nal)k(nle)-NH 2 (D2D) with promising antimicrobial activity. In this work, we have performed a structure-activity relationship study of D2D based on 36 analogues aimed at discovering which elements are important for antimicrobial activity and toxicity. These modifications include an alanine scan, probing variation of hydrophobicity at lys 5 and lys 7 , manipulation of amphipathicity, N-and C-termini deletions and lys-arg substitutions. We found that the hydrophobic residues in position 3 (1-nal), 4 (phe), 6 (1-nal) and 8 (nle) are important for antimicrobial activity and to a lesser extent cationic lysine residues in position 1, 2, 5 and 7. Our best analogue 5, showed MICs of 4 µg/mL against A. baumannii, E. coli, P. aeruginosa and S. aureus with a hemolytic activity of 47% against red blood cells. Furthermore, compound 5 kills bacteria in a concentration-dependent manner as shown by time-kill kinetics. Circular dichroism (CD) spectra of D2D and compounds 1-8 showed that they likely fold into α-helical secondary structure. Small angle x-ray scattering (SAXS) experiments showed that a random unstructured polymer-like chains model could explain D2D and compounds 1, 3, 4, 6 and 8. Solution structure of compound 5 can be described with a nanotube structure model, compound 7 can be described with a filament-like structure model, while compound 2 can be described with both models. Lipid interaction probed by small angle X-ray scattering (SAXS) showed that a higher amount of compound 5 (~50-60%) inserts into the bilayer compared to D2D (~30-50%). D2D still remains the lead compound, however compound 5 is an interesting antimicrobial peptide for further investigations due to its nanotube structure and minor improvement to antimicrobial activity compared to D2D.

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Comparative functional properties of engineered cationic antimicrobial peptides consisting exclusively of tryptophan and either lysine or arginine

Cited by 40 publications

References 66 publications

Membrane Active Peptides and Their Biophysical Characterization

Membrane Active Peptides and Their Biophysical Characterization

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

Structure-Activity Study of an All-d Antimicrobial Octapeptide D2D

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