Effect of Lysine Side Chain Length on Intra-Helical Glutamate−Lysine Ion Pairing Interactions

Cheng, Richard P.; Girinath, Prashant; Ahmad, Raheel

doi:10.1021/bi700701z

Cited by 28 publications

(52 citation statements)

References 77 publications

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“…This trend is identical to that reported for the parent C18G peptide [ 32 ]. Notably, the C18G-Dap peptide exhibited somewhat less helical character compared to the other peptides, which has been reported previously [ 38 ]. A comparison of the spectra of all peptides bound to PC/PG vesicles is shown in Figure 3 F.…”

Section: Resultssupporting

confidence: 75%

Role of Cationic Side Chains in the Antimicrobial Activity of C18G

et al. 2018

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Antimicrobial peptides (AMPs) have been an area of great interest, due to the high selectivity of these molecules toward bacterial targets over host cells and the limited development of bacterial resistance to these molecules throughout evolution. The peptide C18G has been shown to be a selective, broad spectrum AMP with a net +8 cationic charge from seven lysine residues in the sequence. In this work, the cationic Lys residues were replaced with other natural or non-proteinogenic cationic amino acids: arginine, histidine, ornithine, or diaminopropionic acid. These changes vary in the structure of the amino acid side chain, the identity of the cationic moiety, and the pKa of the cationic group. Using a combination of spectroscopic and microbiological methods, the influence of these cationic groups on membrane binding, secondary structure, and antibacterial activity was investigated. The replacement of Lys with most other cationic residues had, at most, 2-fold effects on minimal inhibitory concentration against a variety of Gram-positive and Gram-negative bacteria. However, the peptide containing His as the cationic group showed dramatically reduced activity. All peptide variants retained the ability to bind lipid vesicles and showed clear preference for binding vesicles that contained anionic lipids. Similarly, all peptides adopted a helical conformation when bound to lipids or membrane mimetics, although the peptide containing diaminopropionic acid exhibited a decreased helicity. The peptides exhibited a wider variety of activity in the permeabilization of bacterial membranes, with peptides containing Lys, Arg, or Orn being the most broadly active. In all, the antibacterial activity of the C18G peptide is generally tolerant to changes in the structure and identity of the cationic amino acids, yielding new possibilities for design and development of AMPs that may be less susceptible to immune and bacterial recognition or in vivo degradation.

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Section: Resultssupporting

confidence: 75%

Role of Cationic Side Chains in the Antimicrobial Activity of C18G

et al. 2018

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“…7). 62 Cyclic analogues 16 and 18 also proved to have more helical character than the parent compound 1, and more than linear precursors 15 and 17. As already mentioned, cyclic peptide 16 is the best compound within this collection in terms of affinity for the VEGFR-1.…”

Section: Discussionmentioning

confidence: 96%

Helical peptides from VEGF and Vammin hotspots for modulating the VEGF–VEGFR interaction

et al. 2013

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aThe design, synthesis, conformational studies and binding affinity for VEGF receptors of a collection of linear and cyclic peptide analogues of the N-terminal α-helix fragments 13-25 of VEGF and 1-13 of Vammin are described. Linear 13(14)-mer peptides were designed with the help of an AGADIR algorithm and prepared following peptide solid-phase synthetic protocols. Cyclic peptide derivatives were prepared on-resin from linear precursors with conveniently located Glu and Lys residues, by the formation of amide linkages. Conformational analysis, CD and NMR, showed that most synthesized peptides have a clear tendency to be structured as α-helices in solution. Some of the peptides were able to bind a VEGFR-1 receptor with moderate affinity. In addition to the described key residues (Phe17, Tyr21 and Tyr25), Val14 and Val20 seem to be relevant for affinity.

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“…This is not unexpected as previous reports have shown inclusion of Dap reduces helical content. [50] However, this will directly impact the way the peptide orients on/in the bilayer, potentially reducing the role of the facial amphiphilicity of the AMP structure.…”

Section: Discussionmentioning

confidence: 99%

Antimicrobial activity of a porphyrin binding peptide

et al. 2018

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Amphiphilic alpha-helices are common motifs used in numerous biological systems including membrane channels/pores and antimicrobial peptides (AMPs), and binding proteins, and a variety of synthetic biomaterials. Previously, an amphiphilic peptide with lysine-containing motifs was shown to reversibly bind the anionic porphyrin meso-Tetra(4-sulfonatophenyl)porphyrin (TPPS42−) and promote the formation of excitonically coupled conductive J-aggregates. The work presented here focuses on the use of this amphiphilic peptide and derivatives as a potential antimicrobial agent. AMPs are naturally occurring components of the innate immune system, which selectively target and kill bacteria. Sequence derivatives were synthesized in which the position of the Trp, used as a fluorescence reporter, was changed. Additional variants were synthesized where the hydrophobic amino acids were replaced with Ala to reduce net hydrophobicity or where the cationic Lys residues were replaced with diaminopropionic acid (Dap). All peptide sequences retained the ability to bind TPPS42− and promote the formation of J-aggregates. The peptides all exhibited a preference for binding anionic lipid vesicles compared to zwitterionic bilayers. The Trp position did not impact antimicrobial activity, but the substituted peptides exhibited markedly lower efficacy. The Dap-containing peptide was only active against E. coli and P. aeruginosa, while the Ala-substituted peptide was inactive at the concentrations tested. This trend was also evident in bacterial membrane permeabilization. The results indicate that the amphiphilic porphyrin binding peptides can also be used as antimicrobial peptides. The cationic nature is a driver in binding to lipid bilayers, but the overall hydrophobicity is important for antimicrobial activity and membrane disruption.

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Effect of Lysine Side Chain Length on Intra-Helical Glutamate−Lysine Ion Pairing Interactions

Cited by 28 publications

References 77 publications

Role of Cationic Side Chains in the Antimicrobial Activity of C18G

Role of Cationic Side Chains in the Antimicrobial Activity of C18G

Helical peptides from VEGF and Vammin hotspots for modulating the VEGF–VEGFR interaction

Antimicrobial activity of a porphyrin binding peptide

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