D-amino acid substitution enhances the stability of antimicrobial peptide polybia-CP
D-amino acid substitution enhances the stability of antimicrobial peptide polybia-CP
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D-氨基酸取代增强抗菌肽polybia-CP的稳定性
DOI：
10.1093/abbs/gmx091
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发表时间：
2017-10-01
影响因子：
3.7
通讯作者：
Wang, Rui
中科院分区：
文献类型：
--
作者：
Jia, Fengjing;Wang, Jiayi;Wang, Rui
随着越来越多的微生物对常规抗菌剂产生耐药，迫切需要开发具有新型作用模式的抗菌剂。抗菌肽(AMPs)被认为是一种理想的替代物。然而，AMPS很容易被酶降解，限制了其治疗作用。本研究采用D-氨基酸取代策略来提高Polybia-CP的稳定性。我们通过测定多肽的抗菌活性或测定多肽与蛋白水解酶孵育后的高效液相图谱，考察了多肽对胰酶和胰凝乳酶降解的稳定性。结果表明，全D-氨基酸衍生物(D-CP)和部分D-赖氨酸取代衍生物(D-Lys-CP)对胰酶和胰凝乳酶均有较好的稳定性。虽然D-CP具有左侧α-螺旋构象，D-赖氨酸-CP失去了部分α-螺旋含量，但这两种D-氨基酸取代的衍生物都保持了其亲本多肽的膜活性作用模式。此外，D-Lys-CP的抗菌活性略弱于Polybia-CP，但其溶血活性明显降低。这些结果表明，D-CP和D-Lys-CP可以为改善AMPS的性能提供策略，并可能成为开发新型抗菌剂的先导化合物。
With the increasing emergence of resistant microbes toward conventional antimicrobial agents, there is an urgent need for the development of antimicrobial agents with novel action mode. Antimicrobial peptides (AMPs) are believed to be one kind of ideal alternatives. However, AMPs can be easily degraded by protease, which limited their therapeutic use. In the present study, D-amino acid substitution strategy was employed to enhance the stability of polybia-CP. We investigated the stability of peptides against the degradation of trypsin and chymotrypsin by determining the antimicrobial activity or determining the HPLC profile of peptides after incubation with proteases. Our results showed that both the all D-amino acid derivative (D-CP) and partial D-lysine substitution derivative (D-lys-CP) have an improved stability against trypsin and chymotrypsin. Although D-CP takes left-hand α-helical conformation and D-lys-CP loses some α-helical content, both of the D-amino acid-substituted derivatives maintain their parental peptides' membrane active action mode. In addition, D-lys-CP showed a slight weaker antimicrobial activity than polybia-CP, but the hemolytic activity decreased greatly. These results suggest that D-CP and D-lys-CP can offer strategy to improve the property of AMPs and may be leading compounds for the development of novel antimicrobial agents.