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Liposome fusion with orthogonal coiled coil peptides as fusogens: the efficacy of roleplaying peptides
Chemical Science ( IF 7.6 ) Pub Date : 2021-09-22 , DOI: 10.1039/d0sc06635d Geert A Daudey 1 , Mengjie Shen 1 , Ankush Singhal 1 , Patrick van der Est 1 , G J Agur Sevink 1 , Aimee L Boyle 2 , Alexander Kros 1
Chemical Science ( IF 7.6 ) Pub Date : 2021-09-22 , DOI: 10.1039/d0sc06635d Geert A Daudey 1 , Mengjie Shen 1 , Ankush Singhal 1 , Patrick van der Est 1 , G J Agur Sevink 1 , Aimee L Boyle 2 , Alexander Kros 1
Affiliation
Biological membrane fusion is a highly specific and coordinated process as a multitude of vesicular fusion events proceed simultaneously in a complex environment with minimal off-target delivery. In this study, we develop a liposomal fusion model system with specific recognition using lipidated derivatives of a set of four de novo designed heterodimeric coiled coil (CC) peptide pairs. Content mixing was only obtained between liposomes functionalized with complementary peptides, demonstrating both fusogenic activity of CC peptides and the specificity of this model system. The diverse peptide fusogens revealed important relationships between the fusogenic efficacy and the peptide characteristics. The fusion efficiency increased from 20% to 70% as affinity between complementary peptides decreased, (from KF ≈ 108 to 104 M−1), and fusion efficiency also increased due to more pronounced asymmetric role-playing of membrane interacting ‘K’ peptides and homodimer-forming ‘E’ peptides. Furthermore, a new and highly fusogenic CC pair (E3/P1K) was discovered, providing an orthogonal peptide triad with the fusogenic CC pairs P2E/P2K and P3E/P3K. This E3/P1k pair was revealed, via molecular dynamics simulations, to have a shifted heptad repeat that can accommodate mismatched asparagine residues. These results will have broad implications not only for the fundamental understanding of CC design and how asparagine residues can be accommodated within the hydrophobic core, but also for drug delivery systems by revealing the necessary interplay of efficient peptide fusogens and enabling the targeted delivery of different carrier vesicles at various peptide-functionalized locations.
中文翻译:
脂质体与正交卷曲螺旋肽作为融合剂融合:角色扮演肽的功效
生物膜融合是一个高度特异性和协调的过程,因为许多囊泡融合事件在复杂的环境中同时进行,且脱靶率极低。在这项研究中,我们使用一组四个从头设计的异二聚体卷曲螺旋 (CC) 肽对的脂化衍生物开发了一种具有特异性识别的脂质体融合模型系统。内容混合仅在用互补肽功能化的脂质体之间获得,证明了 CC 肽的融合活性和该模型系统的特异性。不同的肽融合剂揭示了融合功效与肽特性之间的重要关系。随着互补肽之间的亲和力降低,融合效率从 20% 增加到 70%,(从K F ≈ 10 8到10 4 M -1 ),并且由于膜相互作用的“K”肽和形成同源二聚体的“E”肽的更显着的不对称角色扮演,融合效率也增加。此外,还发现了一个新的高融合性 CC 对 (E 3 /P1 K ),提供了具有融合性 CC 对 P2 E /P2 K和 P3 E /P3 K的正交肽三联体。这对 E 3 /P1 k被揭示,通过分子动力学模拟,具有可容纳错配天冬酰胺残基的移位七肽重复序列。这些结果不仅对 CC 设计的基本理解以及如何将天冬酰胺残基容纳在疏水核心内,而且通过揭示有效肽融合剂的必要相互作用和实现不同载体的靶向递送对药物递送系统具有广泛的意义。不同肽功能化位置的囊泡。
更新日期:2021-09-30
中文翻译:
脂质体与正交卷曲螺旋肽作为融合剂融合:角色扮演肽的功效
生物膜融合是一个高度特异性和协调的过程,因为许多囊泡融合事件在复杂的环境中同时进行,且脱靶率极低。在这项研究中,我们使用一组四个从头设计的异二聚体卷曲螺旋 (CC) 肽对的脂化衍生物开发了一种具有特异性识别的脂质体融合模型系统。内容混合仅在用互补肽功能化的脂质体之间获得,证明了 CC 肽的融合活性和该模型系统的特异性。不同的肽融合剂揭示了融合功效与肽特性之间的重要关系。随着互补肽之间的亲和力降低,融合效率从 20% 增加到 70%,(从K F ≈ 10 8到10 4 M -1 ),并且由于膜相互作用的“K”肽和形成同源二聚体的“E”肽的更显着的不对称角色扮演,融合效率也增加。此外,还发现了一个新的高融合性 CC 对 (E 3 /P1 K ),提供了具有融合性 CC 对 P2 E /P2 K和 P3 E /P3 K的正交肽三联体。这对 E 3 /P1 k被揭示,通过分子动力学模拟,具有可容纳错配天冬酰胺残基的移位七肽重复序列。这些结果不仅对 CC 设计的基本理解以及如何将天冬酰胺残基容纳在疏水核心内,而且通过揭示有效肽融合剂的必要相互作用和实现不同载体的靶向递送对药物递送系统具有广泛的意义。不同肽功能化位置的囊泡。