Optimizing charge switching in membrane lytic peptides for endosomal release of biomacromolecules.
Optimizing charge switching in membrane lytic peptides for endosomal release of biomacromolecules.
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DOI：
10.1002/anie.202005887
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发表时间：
2020-06
影响因子：
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通讯作者：
K. Sakamoto;Misao Akishiba;Takahiro Iwata;Kazuya Murata;S. Mizuno;Kenichi Kawano;M. Imanishi;F. Sugiyama;S. Futaki
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文献类型：
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作者：
K. Sakamoto;Misao Akishiba;Takahiro Iwata;Kazuya Murata;S. Mizuno;Kenichi Kawano;M. Imanishi;F. Sugiyama;S. Futaki
内吞途径是生物大分子在细胞内传递的实用途径。与此同时，需要有效的策略将内体货物释放到细胞质中以实现成功的递送。针对细胞和内体膜的组成差异以及内体内pH值的降低，我们设计了脂敏感和pH响应的内体裂解肽HAad。这种肽含有氨基己二酸（Aad）残基，作为一种安全捕获物，使内体膜优先穿透细胞膜，并通过His-to-Ala取代来增强内体溶解活性。利用大单层囊泡（LUVs）的模型研究和增加生物大分子（包括抗体）进入活细胞的细胞内递送也支持HAad破坏内体膜稳定的能力。在小鼠模型中，脑室注射含HAad的Cre重组酶导致Cre/loxP重组，显示HAad在体内的潜在适用性。
Endocytic pathways are practical routes for the intracellular delivery of biomacromolecules. Along with this, effective strategies for endosomal cargo release into cytosol are desired to achieve successful delivery. Focused on compositional differences between the cell and endosomal membranes and the pH decrease within endosomes, we designed the lipid-sensitive and pH-responsive endosome lytic peptide HAad. This peptide contains aminoadipic acid (Aad) residues, which serve as a safety-catch for preferential permeabilization of endosomal membranes over cell membranes, and His-to-Ala substitutions to enhance the endosomolytic activity. The ability of HAad to destabilize endosomal membranes was also supported by the model studies using large unilamellar vesicles (LUVs) and by increased intracellular delivery of biomacromolecules (including antibodies) into live cells. Cerebral ventricle injection of Cre recombinase with HAad led to Cre/loxP recombination in a mouse model, showing potential applicability of HAad in vivo.