探索生物相容性化学,创造抗菌肽aurein 1.2的缝合和光开关变体。

IF 1.8 4区 生物学 Q4 BIOCHEMISTRY & MOLECULAR BIOLOGY
Alexandra E. Coram, Richard Morewood, Saan Voss, Joshua L. Price, Christoph Nitsche
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引用次数: 0

摘要

抗生素耐药性是一个不断升级的全球健康威胁。由于其作用机制的多样性和对传统耐药性机制的逃避,肽有望成为未来的抗生素。它们破坏细菌膜的能力为对抗耐药性感染和解决日益增长的有效抗菌治疗需求提供了一种潜在的策略。两亲性α-螺旋肽具有独特的分子结构,具有带电/亲水和疏水区域,与细菌细胞膜相互作用,破坏其结构完整性。澳大利亚蛙Litoria aurea分泌的α-螺旋两亲肽aurein 1.2是已知最短的抗菌肽之一,仅跨越13个氨基酸。本研究的主要目的是利用aurein 1.2作为模型系统,利用生物相容性化学研究短螺旋肽的缝合和光开关修饰。我们利用二氰基吡啶和1,2-氨基硫醇之间的生物相容性偶联化学,开发了各种aurein 1.2的缝合版本。虽然长钉常用的装订模式是i,i + 7,我们在缝合在位置i,i的肽中观察到优越的螺旋性 + 8.分子动力学模拟证实了两种吻合模式都支持α-螺旋肽构象。此外,我们利用半胱氨酸选择性光敏主食全氟偶氮苯来探索aurein 1.2的可光开关变体。一个双半胱氨酸变异体钉在i,i + 7确实表现出由光诱导的整体螺旋度的变化。我们进一步证明了这种主食附着在i,i中半胱氨酸残基上的适用性 + 模型蛋白质中螺旋的7个位置。虽然一些缝合的变体显示出螺旋度的显著增加,但最小抑制浓度测定显示,与野生型相比,没有任何缝合的aurein 1.2变体显示出增加的抗菌活性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Exploring biocompatible chemistry to create stapled and photoswitchable variants of the antimicrobial peptide aurein 1.2

Exploring biocompatible chemistry to create stapled and photoswitchable variants of the antimicrobial peptide aurein 1.2

Exploring biocompatible chemistry to create stapled and photoswitchable variants of the antimicrobial peptide aurein 1.2

Antibiotic resistance is an escalating global health threat. Due to their diverse mechanisms of action and evasion of traditional resistance mechanisms, peptides hold promise as future antibiotics. Their ability to disrupt bacterial membranes presents a potential strategy to combat drug-resistant infections and address the increasing need for effective antimicrobial treatments. Amphipathic α-helical peptides possess a distinctive molecular structure with both charged/hydrophilic and hydrophobic regions that interact with the bacterial cell membrane, disrupting its structural integrity. The α-helical amphipathic peptide aurein 1.2, secreted by the Australian frog Litoria aurea, is one of the shortest known antimicrobial peptides, spanning only 13 amino acids. The primary objective of this study was to investigate stapled and photoswitchable modifications of short helical peptides employing biocompatible chemistry, utilising aurein 1.2 as a model system. We developed various stapled versions of aurein 1.2 using biocompatible conjugation chemistry between dicyanopyridine and 1,2-aminothiols. While the commonly employed stapling pattern for longer staples is i, i + 7, we observed superior helicity in peptides stapled at positions i, i + 8. Molecular dynamics simulations confirmed both stapling patterns to support an α-helical peptide conformation. Additionally, we utilised a cysteine-selective photosensitive staple, perfluoro azobenzene, to explore photoswitchable variants of aurein 1.2. A double-cysteine variant stapled at i, i + 7 indeed exhibited a change in overall helicity induced by light. We further demonstrated the applicability of this staple to attach to cysteine residues in i, i + 7 positions of a helix in a model protein. While some of the stapled variants displayed substantial increase in helicity, minimal inhibitory concentration assays revealed that none of the stapled aurein 1.2 variants exhibited increased antimicrobial activity compared to the wildtype.

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来源期刊
Journal of Peptide Science
Journal of Peptide Science 生物-分析化学
CiteScore
3.40
自引率
4.80%
发文量
83
审稿时长
1.7 months
期刊介绍: The official Journal of the European Peptide Society EPS The Journal of Peptide Science is a cooperative venture of John Wiley & Sons, Ltd and the European Peptide Society, undertaken for the advancement of international peptide science by the publication of original research results and reviews. The Journal of Peptide Science publishes three types of articles: Research Articles, Rapid Communications and Reviews. The scope of the Journal embraces the whole range of peptide chemistry and biology: the isolation, characterisation, synthesis properties (chemical, physical, conformational, pharmacological, endocrine and immunological) and applications of natural peptides; studies of their analogues, including peptidomimetics; peptide antibiotics and other peptide-derived complex natural products; peptide and peptide-related drug design and development; peptide materials and nanomaterials science; combinatorial peptide research; the chemical synthesis of proteins; and methodological advances in all these areas. The spectrum of interests is well illustrated by the published proceedings of the regular international Symposia of the European, American, Japanese, Australian, Chinese and Indian Peptide Societies.
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