Abstract：
The rational design modification of membrane-active peptide structures by introducing additional membrane-penetrating regions has become a good strategy for the improvement of action and potency. Aurein 1.2 (GLFDIIKKIAESF-NH2) is a multifunctional antimicrobial peptide isolated from the green and golden bell frog, Litoria aurea, and the southern bell frog Litoria raniformis skin secretions. Its bio-functionality has been widely investigated. However, its lack of a potent action failed to provide aurein 1.2 with a competitive edge for further development as a therapeutic agent for clinical use. Herein, aurein 1.2 was chosen as a template for rational modification to achieve a more potent bio-functionality. KLA-2 (GLFDIIKKLAKLAESF-NH2), which a double KLA region inserted into the sequence, presented a 2-16-fold enhancement of antimicrobial activity, a 2-8-fold greater anti-biofilm activity (including biofilm prevention and eradication), and a 7-fold more potent anti-proliferation activity and hence was regarded as the most broad-spectrum active peptide. Additionally, with respect to antimicrobial activity, the IIKK-modified analog, IK-3 (GLFDIIKKIIKKIIKKI-NH2), also demonstrated a potent enhancement of activity against various pathogens, exhibiting a 2-8-fold enhanced activity compared to the parent peptide. Moreover, the selectivities of KLA-1 and KLA-2 were enhanced significantly. In conclusion, peptide modification, through the introduction of additional membrane penetrating regions, can increase both the potency and activity spectra of natural template peptides, making them suitable candidates for new drug development.
摘要：
通过引入额外的膜穿透区域对膜活性肽结构进行合理设计修饰已成为改善作用和效力的良好策略。Aurein1.2（GLFDIIKKIAESF-NH2）是一种多功能的抗菌肽，分离自绿色和金色的铃蛙，利托利亚澳大利亚,和南部的铃蛙Litoriaraniformis皮肤分泌物。其生物功能已被广泛研究。然而,它缺乏有效的作用，未能为进一步开发临床治疗药物提供竞争优势。在这里，选择aurein1.2作为合理修饰的模板，以实现更有效的生物功能。KLA-2（GLFDIIKKLAKLAESF-NH2），将双KLA区插入到序列中，表现出2-16倍的抗菌活性增强，2-8倍以上的抗生物膜活性（包括生物膜预防和根除），和7倍更有效的抗增殖活性，因此被认为是最广谱的活性肽。此外,关于抗菌活性，IIKK修饰的类似物，IK-3(GLFDIIKKIIKIIKIKKI-NH2)，还证明了对各种病原体的活性的有效增强，表现出与亲本肽相比2-8倍增强的活性。此外，KLA-1和KLA-2的选择性显著提高。总之,肽修饰，通过引入额外的膜穿透区域，可以增加天然模板肽的效力和活性谱，使它们成为新药开发的合适人选。
