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High specific selectivity and Membrane-Active Mechanism of the synthetic centrosymmetric α-helical peptides with Gly-Gly pairs.

Wang J, Chou S, Xu L, Zhu X, Dong N, Shan A, Chen Z - Sci Rep (2015)

Bottom Line: However, there is little research describing such design ideas for synthetic α-helical peptides.Therefore, here, we established a centrosymmetric α-helical sequence template (y + hhh + y)n (h, hydrophobic amino acid; +, cationic amino acid; y, Gly or hydrophobic amino acid), which contributed to amphipathicity, and a series of centrosymmetric peptides was designed with pairs of small amino acids (Ala and Gly), which were utilized to modulate the biological activity.Collectively, the Gly-rich centrosymmetric peptide GG3 was an ideal candidate for commercialization as a clinical therapeutic to treat gram-negative bacterial infections.

View Article: PubMed Central - PubMed

Affiliation: Institute of Animal Nutrition, Northeast Agricultural University, Harbin 150030, P.R. China.

ABSTRACT
We used a template-assisted approach to develop synthetic antimicrobial peptides, which differ from naturally occurring antimicrobial peptides that can compromise host natural defenses. Previous researches have demonstrated that symmetrical distribution patterns of amino acids contribute to the antimicrobial activity of natural peptides. However, there is little research describing such design ideas for synthetic α-helical peptides. Therefore, here, we established a centrosymmetric α-helical sequence template (y + hhh + y)n (h, hydrophobic amino acid; +, cationic amino acid; y, Gly or hydrophobic amino acid), which contributed to amphipathicity, and a series of centrosymmetric peptides was designed with pairs of small amino acids (Ala and Gly), which were utilized to modulate the biological activity. The centrosymmetric peptides with 3 repeat units exhibited strong antimicrobial activity; in particular, the Gly-rich centrosymmetric peptide GG3 showed stronger selectivity for gram-negative bacteria without hemolysis. Furthermore, beyond our expectation, fluorescence spectroscopy and electron microscopy analyses indicated that the GG3, which possessed poor α-helix conformation, dramatically exhibited marked membrane destruction via inducing bacterial membrane permeabilization, pore formation and disruption, even bound DNA to further exert antimicrobial activity. Collectively, the Gly-rich centrosymmetric peptide GG3 was an ideal candidate for commercialization as a clinical therapeutic to treat gram-negative bacterial infections.

No MeSH data available.


Related in: MedlinePlus

The security of the centrosymmetric peptides.(A) Hemolytic activity of the centrosymmetric peptides against hRBCs. (B) Cytotoxicity of the centrosymmetric peptides against RAW 264.7 cells. The graphs were derived from average values of three independent trials. P** < 0.01, compared to the values of GG2, GG3 and GG4, respectively at the same concentration. Means in the same concentration with different superscript are very significant difference (P < 0.01).
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f2: The security of the centrosymmetric peptides.(A) Hemolytic activity of the centrosymmetric peptides against hRBCs. (B) Cytotoxicity of the centrosymmetric peptides against RAW 264.7 cells. The graphs were derived from average values of three independent trials. P** < 0.01, compared to the values of GG2, GG3 and GG4, respectively at the same concentration. Means in the same concentration with different superscript are very significant difference (P < 0.01).

Mentions: The toxicity of the peptides against hRBCs and RAW264.7 macrophage cells was evaluated at serial peptide concentrations in the range of 1–128 μM. It is desirable that GG2 and GG3 very significantly reduced hemolytic activity and cytotoxic activity compared with AA2 and AA3 (P < 0.01), respectively, at the highest concentration (Fig. 2). And as the same with GG3, GG3s1 and GG3s2 also kept weak cytotoxicity towards eukaryotic cells. Instead, the cell toxicity of AA3s1 was still high at 128 μM, but it was very significantly lowered compared with AA3 between 8 μM and 64 μM (P < 0.01) (Supplementary Fig. S3).


High specific selectivity and Membrane-Active Mechanism of the synthetic centrosymmetric α-helical peptides with Gly-Gly pairs.

Wang J, Chou S, Xu L, Zhu X, Dong N, Shan A, Chen Z - Sci Rep (2015)

The security of the centrosymmetric peptides.(A) Hemolytic activity of the centrosymmetric peptides against hRBCs. (B) Cytotoxicity of the centrosymmetric peptides against RAW 264.7 cells. The graphs were derived from average values of three independent trials. P** < 0.01, compared to the values of GG2, GG3 and GG4, respectively at the same concentration. Means in the same concentration with different superscript are very significant difference (P < 0.01).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4632126&req=5

f2: The security of the centrosymmetric peptides.(A) Hemolytic activity of the centrosymmetric peptides against hRBCs. (B) Cytotoxicity of the centrosymmetric peptides against RAW 264.7 cells. The graphs were derived from average values of three independent trials. P** < 0.01, compared to the values of GG2, GG3 and GG4, respectively at the same concentration. Means in the same concentration with different superscript are very significant difference (P < 0.01).
Mentions: The toxicity of the peptides against hRBCs and RAW264.7 macrophage cells was evaluated at serial peptide concentrations in the range of 1–128 μM. It is desirable that GG2 and GG3 very significantly reduced hemolytic activity and cytotoxic activity compared with AA2 and AA3 (P < 0.01), respectively, at the highest concentration (Fig. 2). And as the same with GG3, GG3s1 and GG3s2 also kept weak cytotoxicity towards eukaryotic cells. Instead, the cell toxicity of AA3s1 was still high at 128 μM, but it was very significantly lowered compared with AA3 between 8 μM and 64 μM (P < 0.01) (Supplementary Fig. S3).

Bottom Line: However, there is little research describing such design ideas for synthetic α-helical peptides.Therefore, here, we established a centrosymmetric α-helical sequence template (y + hhh + y)n (h, hydrophobic amino acid; +, cationic amino acid; y, Gly or hydrophobic amino acid), which contributed to amphipathicity, and a series of centrosymmetric peptides was designed with pairs of small amino acids (Ala and Gly), which were utilized to modulate the biological activity.Collectively, the Gly-rich centrosymmetric peptide GG3 was an ideal candidate for commercialization as a clinical therapeutic to treat gram-negative bacterial infections.

View Article: PubMed Central - PubMed

Affiliation: Institute of Animal Nutrition, Northeast Agricultural University, Harbin 150030, P.R. China.

ABSTRACT
We used a template-assisted approach to develop synthetic antimicrobial peptides, which differ from naturally occurring antimicrobial peptides that can compromise host natural defenses. Previous researches have demonstrated that symmetrical distribution patterns of amino acids contribute to the antimicrobial activity of natural peptides. However, there is little research describing such design ideas for synthetic α-helical peptides. Therefore, here, we established a centrosymmetric α-helical sequence template (y + hhh + y)n (h, hydrophobic amino acid; +, cationic amino acid; y, Gly or hydrophobic amino acid), which contributed to amphipathicity, and a series of centrosymmetric peptides was designed with pairs of small amino acids (Ala and Gly), which were utilized to modulate the biological activity. The centrosymmetric peptides with 3 repeat units exhibited strong antimicrobial activity; in particular, the Gly-rich centrosymmetric peptide GG3 showed stronger selectivity for gram-negative bacteria without hemolysis. Furthermore, beyond our expectation, fluorescence spectroscopy and electron microscopy analyses indicated that the GG3, which possessed poor α-helix conformation, dramatically exhibited marked membrane destruction via inducing bacterial membrane permeabilization, pore formation and disruption, even bound DNA to further exert antimicrobial activity. Collectively, the Gly-rich centrosymmetric peptide GG3 was an ideal candidate for commercialization as a clinical therapeutic to treat gram-negative bacterial infections.

No MeSH data available.


Related in: MedlinePlus