Limits...
Cationic Antimicrobial Peptides (AMPs): Thermodynamic Characterization of Peptide-Lipid Interactions and Biological Efficacy of Surface-Tethered Peptides.

Bagheri M - ChemistryOpen (2015)

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry, Institute of Biochemistry & Biophysics, University of Tehran P.O. Box: 13145-1365, 16 Azar St., 1417614411, Tehran, Iran.

AUTOMATICALLY GENERATED EXCERPT
Please rate it.

Unlike the cholesterol-rich electrically neutral lipid membrane of eukaryotic cells, responsible for low peptide affinity and insertion, the bacterial cytoplasmic membrane possesses negatively charged phospholipids that, together with additional cellular envelope features such as the lipopolysaccharide (LPS) and peptidoglycans in Gram-negative and Gram-positive bacteria, respectively, represent ideal targets for cationic AMPs binding... In this doctoral research, the structural basis of activity of short cyclic AMPs rich in arginine and tryptophan residues, as promising anti-E.  coli candidates, was studied to understand membrane constituents and the peptide structural motif important for selectivity against Gram-negative bacteria... In particular, we sought to understand how a) the physical properties of the resin, such as the spacer length between the solid matrix and the AMP, as well as the capacity of the functional groups on the surface, and b) the tethering at different positions (peptide termini and side chain) affect the activities of the tethered AMPs. cyclo-RRRWFW (c-WFW) shows excellent activities against various strains of bacteria (in particular Gram-negative such as E.  coli) compared with its linear analogue, Ac-RRRWFW (Ac-WFW)... The roles of both the arginine and tryptophan residues in biological and bilayer permeabilizing activities are described for several peptide variants... The susceptibility of Gram-negative bacteria to c-WFW was proposed to be associated with factors that facilitate the transport of the peptide across the LPS. c-WFW is most active against the smooth LPS strain (wild type), while reduction of sugar chains in mutated LPS strain (rough type) distinctly decreases the antimicrobial effect... While the significant role of tryptophan residues in many LPS-binding motifs of AMPs is known, studies on the structural motifs of c-WFW in particular from the point of selective interactions between the aromatic side chain of tryptophan residues and distinct regions of LPS, which are important for its anti-E.  coli activity, needed to be done... In the presence of lipid A, rough-LPS and smooth-LPS, the dominant role of hydrophobicity decreased among the cyclic peptides with no influence on the weak affinity of the highly flexible linear Ac-WFW... The higher hydrophobic partition coefficients for the peptide interaction with POPC/smooth-LPS compared with POPC/rough-LPS lipid bilayers underlined the modulating effects of the O-antigen and the oligosaccharides in the outer core of LPS in the peptide activity and transport across the E.  coli outer wall... Specifically, the distance between the solid surface and the active sequences was identified as a critical parameter for peptide activity... The AMPs effectiveness decreased with decreasing spacer length, regardless of the amount of peptide on the surface... Immobilization of membrane-permeabilizing sequences was found to be most suitable for the generation of antimicrobial surfaces... Immobilization did not influence the activity pattern and conserved the peptide membrane-permeabilizing mode of action.

No MeSH data available.


General structure of the cyclic peptides with the positions for desired modifications, and the chemical structures of tryptophan (W) analogues used in this study. Abbreviations: (γS/γR)-dihydrotryptophan (Dht), (αS)-(2-indanyl)glycine (Igl), 5-methoxy-l-tryptophan (5MeoW), 5-fluoro-l-tryptophan (5fW), 5-methyl-d,l-tryptophan (5MeW), 1-methyl-l-tryptophan (1MeW), and β-(benzothien-3-yl)-l-alanine (Bal).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4522190&req=5

sch01: General structure of the cyclic peptides with the positions for desired modifications, and the chemical structures of tryptophan (W) analogues used in this study. Abbreviations: (γS/γR)-dihydrotryptophan (Dht), (αS)-(2-indanyl)glycine (Igl), 5-methoxy-l-tryptophan (5MeoW), 5-fluoro-l-tryptophan (5fW), 5-methyl-d,l-tryptophan (5MeW), 1-methyl-l-tryptophan (1MeW), and β-(benzothien-3-yl)-l-alanine (Bal).

Mentions: While the significant role of tryptophan residues in many LPS-binding motifs of AMPs is known, studies on the structural motifs of c-WFW in particular from the point of selective interactions between the aromatic side chain of tryptophan residues and distinct regions of LPS, which are important for its anti-E. coli activity, needed to be done. For this, a series of c-WFW analogues in which tryptophan residues in the aromatic WFW cluster were substituted with non-natural analogues was synthesized (Scheme 1). These non-natural residues are characterized by altered hydrophobicity, variable dipole and quadrupole moments, modified hydrogen-bonding ability, and changed amphipathicity or enhanced ring size.


Cationic Antimicrobial Peptides (AMPs): Thermodynamic Characterization of Peptide-Lipid Interactions and Biological Efficacy of Surface-Tethered Peptides.

Bagheri M - ChemistryOpen (2015)

General structure of the cyclic peptides with the positions for desired modifications, and the chemical structures of tryptophan (W) analogues used in this study. Abbreviations: (γS/γR)-dihydrotryptophan (Dht), (αS)-(2-indanyl)glycine (Igl), 5-methoxy-l-tryptophan (5MeoW), 5-fluoro-l-tryptophan (5fW), 5-methyl-d,l-tryptophan (5MeW), 1-methyl-l-tryptophan (1MeW), and β-(benzothien-3-yl)-l-alanine (Bal).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4522190&req=5

sch01: General structure of the cyclic peptides with the positions for desired modifications, and the chemical structures of tryptophan (W) analogues used in this study. Abbreviations: (γS/γR)-dihydrotryptophan (Dht), (αS)-(2-indanyl)glycine (Igl), 5-methoxy-l-tryptophan (5MeoW), 5-fluoro-l-tryptophan (5fW), 5-methyl-d,l-tryptophan (5MeW), 1-methyl-l-tryptophan (1MeW), and β-(benzothien-3-yl)-l-alanine (Bal).
Mentions: While the significant role of tryptophan residues in many LPS-binding motifs of AMPs is known, studies on the structural motifs of c-WFW in particular from the point of selective interactions between the aromatic side chain of tryptophan residues and distinct regions of LPS, which are important for its anti-E. coli activity, needed to be done. For this, a series of c-WFW analogues in which tryptophan residues in the aromatic WFW cluster were substituted with non-natural analogues was synthesized (Scheme 1). These non-natural residues are characterized by altered hydrophobicity, variable dipole and quadrupole moments, modified hydrogen-bonding ability, and changed amphipathicity or enhanced ring size.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry, Institute of Biochemistry & Biophysics, University of Tehran P.O. Box: 13145-1365, 16 Azar St., 1417614411, Tehran, Iran.

AUTOMATICALLY GENERATED EXCERPT
Please rate it.

Unlike the cholesterol-rich electrically neutral lipid membrane of eukaryotic cells, responsible for low peptide affinity and insertion, the bacterial cytoplasmic membrane possesses negatively charged phospholipids that, together with additional cellular envelope features such as the lipopolysaccharide (LPS) and peptidoglycans in Gram-negative and Gram-positive bacteria, respectively, represent ideal targets for cationic AMPs binding... In this doctoral research, the structural basis of activity of short cyclic AMPs rich in arginine and tryptophan residues, as promising anti-E.  coli candidates, was studied to understand membrane constituents and the peptide structural motif important for selectivity against Gram-negative bacteria... In particular, we sought to understand how a) the physical properties of the resin, such as the spacer length between the solid matrix and the AMP, as well as the capacity of the functional groups on the surface, and b) the tethering at different positions (peptide termini and side chain) affect the activities of the tethered AMPs. cyclo-RRRWFW (c-WFW) shows excellent activities against various strains of bacteria (in particular Gram-negative such as E.  coli) compared with its linear analogue, Ac-RRRWFW (Ac-WFW)... The roles of both the arginine and tryptophan residues in biological and bilayer permeabilizing activities are described for several peptide variants... The susceptibility of Gram-negative bacteria to c-WFW was proposed to be associated with factors that facilitate the transport of the peptide across the LPS. c-WFW is most active against the smooth LPS strain (wild type), while reduction of sugar chains in mutated LPS strain (rough type) distinctly decreases the antimicrobial effect... While the significant role of tryptophan residues in many LPS-binding motifs of AMPs is known, studies on the structural motifs of c-WFW in particular from the point of selective interactions between the aromatic side chain of tryptophan residues and distinct regions of LPS, which are important for its anti-E.  coli activity, needed to be done... In the presence of lipid A, rough-LPS and smooth-LPS, the dominant role of hydrophobicity decreased among the cyclic peptides with no influence on the weak affinity of the highly flexible linear Ac-WFW... The higher hydrophobic partition coefficients for the peptide interaction with POPC/smooth-LPS compared with POPC/rough-LPS lipid bilayers underlined the modulating effects of the O-antigen and the oligosaccharides in the outer core of LPS in the peptide activity and transport across the E.  coli outer wall... Specifically, the distance between the solid surface and the active sequences was identified as a critical parameter for peptide activity... The AMPs effectiveness decreased with decreasing spacer length, regardless of the amount of peptide on the surface... Immobilization of membrane-permeabilizing sequences was found to be most suitable for the generation of antimicrobial surfaces... Immobilization did not influence the activity pattern and conserved the peptide membrane-permeabilizing mode of action.

No MeSH data available.