Effect of D-amino acid substitution on the stability, the secondary structure, and the activity of membrane-active peptide
Effect of D-amino acid substitution on the stability, the secondary structure, and the activity of membrane-active peptide
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DOI：
10.1016/s0006-2952(99)00259-2
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发表时间：
1999-12-01
影响因子：
5.8
通讯作者：
Lee, KH
中科院分区：
文献类型：
--
作者：
Hong, SY;Oh, JE;Lee, KH
合成了作用于病原体脂质膜的抗菌肽KKVVFKVKFKK的几种非对映异构体和一种对映异构体，以研究D-氨基酸取代对稳定性、二级结构和活性的影响。通过D-氨基酸取代，大大提高了多肽在血清中的稳定性。在肽的N-和/或C-末端的D-氨基酸取代，其对α-螺旋结构几乎没有影响，并且形成左手α-螺旋的所有D-氨基酸取代保持抗微生物活性，而在氨基酸序列中间的D-氨基酸取代破坏α-螺旋结构，导致活性完全丧失。这一结果证实，肽也不与手性受体、酶或膜的任何手性组分相互作用。末端的D-氨基酸取代可减轻热灭活血清对活性的抑制作用，表明D-氨基酸取代引起的局部手性改变或二级结构改变可能影响肽与血清中某些组分的相互作用。本研究表明，部分D-氨基酸取代是改善抗微生物肽BIOCHEM PHARMACOL 58;11：1775-1780，1999体内活性的有用技术。(C)1999 Elsevier Science Inc.
Several diastereomers and an enantiomer of KKVVFKVKFKK, an antimicrobial peptide that acts on the lipid membrane of pathogens were synthesized to investigate the effect of D-amino acid substitution on stability, secondary structure, and activity. The stability of the peptide in serum was improved greatly by the D-amino acid substitutions. D-Amino acid substitutions at the N- and/or C-terminal of the peptide, which had little effect on the alpha-helical structure, and all D-amino acid substitutions that formed a left-handed a-helix maintained antimicrobial activity, whereas D-amino acid substitutions in the middle of the amino acid sequence disrupted the alpha-helical structure, resulting in the complete loss of activity. This result confirmed that the peptide did nor interact with chiral receptors, enzymes, or any chiral component of the membrane. D-Amino acid substitutions at the termini reduced the inhibition of the activity by heat-inactivated serum, which indicated that local change of chirality or change of secondary structure induced by D-amino acid substitutions might affect the interactions between the peptide and certain components in the serum. The present study suggests that partial D-amino acid substitution is a useful technique to improve the in vivo activity of antimicrobial peptides BIOCHEM PHARMACOL 58;11:1775-1780, 1999. (C) 1999 Elsevier Science Inc.