Tuning the biological properties of amphipathic α-helical antimicrobial peptides: Rational use of minimal amino acid substitutions

Zelezetsky, Igor; Pag, Ulrike; Sahl, Hans‐Georg; Tossi, Alessandro

doi:10.1016/j.peptides.2005.05.002

Cited by 73 publications

(68 citation statements)

References 30 publications

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“…Studies have demonstrated that high levels of hydrophobicity can decrease selectivity between the desired bacterial targets and host cells (136,275). Similarly, incorporation of charged residues above a certain maximum (varying with each peptide) does not lead to an increase in activity (46).…”

Section: Structural Requirements For Antibacterial Peptidesmentioning

confidence: 99%

Peptide Antimicrobial Agents

2006

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SUMMARY Antimicrobial host defense peptides are produced by all complex organisms as well as some microbes and have diverse and complex antimicrobial activities. Collectively these peptides demonstrate a broad range of antiviral and antibacterial activities and modes of action, and it is important to distinguish between direct microbicidal and indirect activities against such pathogens. The structural requirements of peptides for antiviral and antibacterial activities are evaluated in light of the diverse set of primary and secondary structures described for host defense peptides. Peptides with antifungal and antiparasitic activities are discussed in less detail, although the broad-spectrum activities of such peptides indicate that they are important host defense molecules. Knowledge regarding the relationship between peptide structure and function as well as their mechanism of action is being applied in the design of antimicrobial peptide variants as potential novel therapeutic agents.

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Section: Structural Requirements For Antibacterial Peptidesmentioning

confidence: 99%

Peptide Antimicrobial Agents

2006

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“…Three libraries were developed for this study: the binary, ␣-helix, and RW libraries. Peptides within the binary and ␣-helix libraries were designed from an amphipathic, ␣-helical sequence arrangement framework (HCCHHCHHCC n , where H is a hydrophobic residue and C is a charged residue) that was developed from several published AMP amphipathic sequence templates (4,46) and was validated using helical-wheel projections (36) and the average helical propensity ϽHelixϾ (Table 1). Figure 1 shows two representative projections from each library.…”

Section: Design Of Constrained Peptide Librariesmentioning

confidence: 99%

Novel Synthetic Antimicrobial Peptides against Streptococcus mutans

He¹,

Eckert

Pharm

et al. 2007

Antimicrob Agents Chemother

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Streptococcus mutans, a common oral pathogen and the causative agent of dental caries, has persisted and even thrived on the tooth surface despite constant removal and eradication efforts. In this study, we generated a number of synthetic antimicrobial peptides against this bacterium via construction and screening of several structurally diverse peptide libraries where the hydrophobicity and charge within each library was varied incrementally in order to generate a collection of peptides with different biochemical characteristics. From these libraries, we identified multiple peptides with robust killing activity against S. mutans. To further improve their effectiveness, the most bactericidal peptides from each library were synthesized together as one molecule, in various combinations, with and without a flexible peptide linker between each antimicrobial region. Many of these "fusion" peptides had enhanced killing activities in comparison with those of the original nonconjoined molecules. The results presented here illustrate that small libraries of biochemically constrained peptides can be used to generate antimicrobial peptides against S. mutans, several of which may be likely candidates for the development of anticaries agents.

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“…The 50% lethal doses (LD 50 ) of C. albicans were further determined as previously described (2) and were 6.9, 1.14, and 1.125 g/ml for P-113, P-113Du, and P-113Tri, respectively. Because reduced LD 50 values may reflect increased cytotoxicity, hemolytic activity was used as an indicator of cytotoxicity (15)(16)(17)(18). The three peptides demonstrated low hemolytic levels and required Ͼ192 g/ml, Ͼ384 g/ml, and Ͼ576 g/ml for P-113, P-113Du, and P-113Tri, respectively, to induce 50% erythrocyte lysis.…”

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The Antimicrobial Peptides P-113Du and P-113Tri Function against Candida albicans

Lin

Chen

Xue

et al. 2016

Antimicrob Agents Chemother

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Two antimicrobial P-113 peptide derivatives, P-113Du and P-113Tri, were investigated in this study. Notably, P-113Du and P-113Tri contained significant fractions of ␣-helix conformation and were less sensitive to high salt and low pH than P-113. Moreover, compared to P-113, these peptides exhibited increased antifungal activity against planktonic cells, biofilm cells, and clinical isolates of Candida albicans and non-albicans Candida spp. These results suggest that P-113Du and P-113Tri are promising candidates for development as novel antifungal agents. Histatin 5 (Hst5) is a potent antimicrobial peptide (AMP) with activity against Candida albicans (1). A 12-mer amino acid fragment of Hst5, P-113, retains strong candidacidal activity compared to the parental Hst5 and has had no adverse effects in clinical trials (2-6). P-113 forms an amphipathic ␣-helix in trifluoroethanol, which mimics the hydrophobic environment of microbial membranes (7). However, the interaction between AMPs and microbial membranes is salt sensitive (8, 9). The efficacy of P-113 is significantly reduced in the presence of high salt concentrations, such as 150 mM sodium chloride or 100 mM sodium phosphate (4, 10).To improve the activity of P-113, our approach was based on the dimerization of histatin-derived peptides to increase bactericidal activity against Staphylococcus aureus (11). In this study, the duplicated and triplicated P-113 (designated P-113Du and P-113Tri, respectively) ( Table 1) were characterized. The secondary structures of the peptides in 85% trifluoroethanol (pH 6.0) were analyzed using an AVIV circular dichroism spectrometer at 25°C. Spectra were measured from 195 to 260 nm at 1-nm intervals, and mean residue molar ellipticity (MRE) was used to compare different peptides. Figure 1 shows an ␣-helical conformation characterized by a strong positive band at 195 nm and two negative bands at 208 and approximately 222 nm (12). The ␣-helical content of P-113 was estimated to be 2.9% using the ␤-structure selection (BeStSel) method (13). However, the ␣-helical contents of P-113Du and P-113Tri were 10.6% and 21.4%, respectively, suggesting the presence of a significant fraction of ␣-helix conformation.To examine the salt sensitivity of the peptides, spot assays were performed ( Fig. 2A). Cells (4.0 ϫ 10 5 cells) of the C. albicans strain SC5314 were incubated with different concentrations of sodium acetate (NaOAc) and peptides for 1 h. The mixtures were then spotted onto 1% yeast extract-2% peptone-2% glucose (YPD) agar. After 24 h of incubation, P-113 exhibited candidacidal activity in the presence of 12.5 mM sodium acetate but reduced activity in the presence of 62.25 and 93.75 mM salt. However, P-113Du and P-113Tri exhibited potent candidacidal activity even in the presence of 93.75 mM sodium acetate ( Fig. 2A). In addition, a previous study indicated that P-113 loses its bactericidal activity at pH 4.5 (14). Therefore, the pH sensitivities of the peptides were examined. P-113 exhibited candidacidal activity at pH 6 and 8, and...

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Tuning the biological properties of amphipathic α-helical antimicrobial peptides: Rational use of minimal amino acid substitutions

Cited by 73 publications

References 30 publications

Peptide Antimicrobial Agents

Peptide Antimicrobial Agents

Novel Synthetic Antimicrobial Peptides against Streptococcus mutans

The Antimicrobial Peptides P-113Du and P-113Tri Function against Candida albicans

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