Multimeric Amphipathic α‐Helical Sequences for Rapid and Efficient Intracellular Protein Transport at Nanomolar Concentrations,Advanced Science

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Multimeric Amphipathic α‐Helical Sequences for Rapid and Efficient Intracellular Protein Transport at Nanomolar Concentrations
Advanced Science ( IF 14.3 ) Pub Date : 2018-06-19 , DOI: 10.1002/advs.201800240
Jae Hoon Oh ₁ , Seung-Eun Chong ₁ , Sohee Nam ₁ , Soonsil Hyun ₂ , Sejong Choi ₁ , Hyojun Gye ₃ , Sangmok Jang ₁ , Joomyung Jang ₁ , Sung Won Hwang ₃ , Jaehoon Yu ₂ , Yan Lee ₁

Affiliation

An amphipathic leucine (L) and lysine (K)‐rich α‐helical peptide is multimerized based on helix‐loop‐helix structures to maximize the penetrating activities. The multimeric LK‐based cell penetrating peptides (LK‐CPPs) can penetrate cells as protein‐fused forms at 100–1000‐fold lower concentrations than Tat peptide. The enhanced penetrating activity is increased through multimerization by degrees up to the tetramer level. The multimeric LK‐CPPs show rapid cell penetration through macropinocytosis at low nanomolar concentrations, unlike the monomeric LK, which have slower penetrating kinetics at much higher concentrations. The heparan sulfate proteoglycan (HSPG) receptors are highly involved in the rapid internalization of multimeric LK‐CPPs. As a proof of concept of biomedical applications, an adipogenic transcription factor, peroxisome proliferator‐activated receptor gamma 2 (PPAR‐γ 2), is delivered into preadipocytes, and highly enhanced expression of adipogenic genes at nanomolar concentrations is induced. The multimeric CPPs can be a useful platform for the intracellular delivery of bio‐macromolecular reagents that have difficulty with penetration in order to control biological reactions in cells at feasible concentrations for biomedical purposes.

中文翻译：

多聚两亲性 α 螺旋序列，用于纳摩尔浓度下快速有效的细胞内蛋白质运输

富含两亲性亮氨酸 (L) 和赖氨酸 (K) 的 α 螺旋肽基于螺旋-环-螺旋结构进行多聚化，以最大限度地提高穿透活性。基于 LK 的多聚体细胞穿透肽 (LK-CPP) 可以以蛋白质融合形式穿透细胞，浓度比 Tat 肽低 100-1000 倍。通过多聚化，增强的穿透活性逐渐增加至四聚体水平。多聚体 LK-CPP 在低纳摩尔浓度下通过巨胞饮作用表现出快速细胞渗透，这与单体 LK 不同，单体 LK 在高浓度下具有较慢的渗透动力学。硫酸乙酰肝素蛋白聚糖 (HSPG) 受体高度参与多聚体 LK-CPP 的快速内化。作为生物医学应用概念的证明，一种脂肪形成转录因子，过氧化物酶体增殖物激活受体γ2（PPAR-γ2），被传递到前脂肪细胞中，并在纳摩尔浓度下诱导脂肪形成基因的高度增强的表达。多聚体 CPP 可以成为细胞内递送难以渗透的生物大分子试剂的有用平台，以便以可行的浓度控制细胞内的生物反应，用于生物医学目的。

更新日期：2018-06-19

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