二级结构对抗菌肽的抗菌活性及特异性的影响
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摘要
我们以15个氨基酸的阳离子型α-螺旋抗菌肽HPRP-A1作为模板研究抗菌肽的二级结构对其抗菌活性和特异性的影响。在不改变原始序列氨基酸组成的情况下，我们通过改变氨基酸的次序，设计了三种具有不同的螺旋能力的α-螺旋的抗菌肽、一个β-折叠抗菌肽和一个无规卷曲抗菌肽，以此体现不同的多肽二级结构。同时，在保留HPRP-A1α-螺旋结构的基础上，通过截断序列长度设计了三个抗菌肽分子。通过圆二色谱测定不同多肽在水溶液中和在疏水环境中二级结构。三种革兰氏阴性细菌，三种的革兰氏阳性细菌和人血红细胞被用于检测抗菌肽的生物活性。结果证实，三个α-螺旋抗菌肽表现出很好的抗菌活性，但他们的溶血效价（毒性），差异明显，与多肽的的螺旋倾向呈正相关。β-折叠抗菌肽部分丧失生物活性。更有趣的是，无规卷曲抗菌肽没有溶血活性，同时针对革兰氏阳性细菌和革兰氏阴性菌的抗菌活性也明显降低。序列截断的抗菌肽不可避免的导致抗菌活性减弱。进一步的NPN实验显示，抗菌肽的抗菌活性与其穿透细菌外膜的能力相关。色氨酸荧光实验揭示，所有的抗菌肽针对原核细胞或真核细胞模拟膜的结合偏好与它们的生物活性相关联。研究结果表明抗菌肽的溶血活性与二级结构呈一定的相关性，但就抗菌活性而言，二级结构对革兰氏阴性菌的影响更加明显。这对进一步解释抗菌肽的作用机制、根据多肽二级结构设计具有应用前景的抗菌肽药物具有重要的作用。
A15-mer cationic α-helical antimicrobial peptide HPRP-A1was used as thetemplate to study the effects of peptide secondary structure on the antimicrobialactivity and specificity. Without changing the original amino acid composition HPRP-A1, we designed three α-helical peptides with either higher or lower helicalpropensity compared with the original peptide, a β-sheet peptide and a random coiledpeptide. Three truncated peptides were also designed. The secondary structures ofpeptides were determined by circular dichroism spectra both in aqueous solution andin hydrophobic environment. The biological activities of peptides were detectedagainst three Gram-negative bacterial strains, three Gram-positive bacterial strainsand human red blood cells. The three helical peptides exhibited comparableantibacterial activities, but their hemolytic potency (cytotoxicity) varied from extremehemolysis to no hemolysis, which was positively correlated with their helicalpropensity. The β-sheet peptide partially lost both of the biological activities. Moreinterestingly, the coiled peptide with no hemolytic activity showed somewhatantibacterial specificity to Gram-positive bacteria because of the considerable loss ofthe antibacterial activity against Gram-negative bacteria. Truncated peptides showedinevitable weaker antimicrobial activity compared to the parent peptide. Furtherinvestigation demonstrated that the antibacterial activity of peptides to Gram-negativebacteria was in accordance with their outer-membrane permeabilizing ability.Tryptophan fluorescence experiment revealed that the binding preference of all ofpeptides to the lipid vesicles for mimicking the cytoplasm of prokaryocyte oreukaryocyte was associated with their biological activity. Our results show thatpeptide secondary structure is strongly correlated with hemolytic activity but lesscorrelated with antimicrobial activity, which providing the insights of mechanism of action of antimicrobial peptide. In this case study, peptide with proper helical contentsmight represent a promising pattern for designing peptide antibiotics.
A15-mer cationic α-helical antimicrobial peptide HPRP-A1was used as thetemplate to study the effects of peptide secondary structure on the antimicrobialactivity and specificity. Without changing the original amino acid composition HPRP-A1, we designed three α-helical peptides with either higher or lower helicalpropensity compared with the original peptide, a β-sheet peptide and a random coiledpeptide. Three truncated peptides were also designed. The secondary structures ofpeptides were determined by circular dichroism spectra both in aqueous solution andin hydrophobic environment. The biological activities of peptides were detectedagainst three Gram-negative bacterial strains, three Gram-positive bacterial strainsand human red blood cells. The three helical peptides exhibited comparableantibacterial activities, but their hemolytic potency (cytotoxicity) varied from extremehemolysis to no hemolysis, which was positively correlated with their helicalpropensity. The β-sheet peptide partially lost both of the biological activities. Moreinterestingly, the coiled peptide with no hemolytic activity showed somewhatantibacterial specificity to Gram-positive bacteria because of the considerable loss ofthe antibacterial activity against Gram-negative bacteria. Truncated peptides showedinevitable weaker antimicrobial activity compared to the parent peptide. Furtherinvestigation demonstrated that the antibacterial activity of peptides to Gram-negativebacteria was in accordance with their outer-membrane permeabilizing ability.Tryptophan fluorescence experiment revealed that the binding preference of all ofpeptides to the lipid vesicles for mimicking the cytoplasm of prokaryocyte oreukaryocyte was associated with their biological activity. Our results show thatpeptide secondary structure is strongly correlated with hemolytic activity but lesscorrelated with antimicrobial activity, which providing the insights of mechanism of action of antimicrobial peptide. In this case study, peptide with proper helical contentsmight represent a promising pattern for designing peptide antibiotics.
引文
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