Multivalent dextran hybrids for efficient cytosolic delivery of biomolecular cargoes,Journal of Peptide Science

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Multivalent dextran hybrids for efficient cytosolic delivery of biomolecular cargoes
Journal of Peptide Science ( IF 1.8 ) Pub Date : 2021-01-17 , DOI: 10.1002/psc.3298
Bastian Becker ₁ , Simon Englert ₁ , Hendrik Schneider ₁ , Desislava Yanakieva ₁ , Sarah Hofmann ₁ , Carolin Dombrowsky ₁ , Arturo Macarrón Palacios ₁ , Sebastian Bitsch ₁ , Adrian Elter _{1,

2} , Tobias Meckel ₂ , Benedikt Kugler ₃ , Anastasyia Schirmacher ₃ , Olga Avrutina ₁ , Ulf Diederichsen ₃ , Harald Kolmar ₁

Affiliation

The development of novel biotherapeutics based on peptides and proteins is often limited to extracellular targets, because these molecules are not able to reach the cytosol. In recent years, several approaches were proposed to overcome this limitation. A plethora of cell‐penetrating peptides (CPPs) was developed for cytoplasmic delivery of cell‐impermeable cargo molecules. For many CPPs, multimerization or multicopy arrangement on a scaffold resulted in improved delivery but also higher cytotoxicity. Recently, we introduced dextran as multivalent, hydrophilic polysaccharide scaffold for multimerization of cell‐targeting cargoes. Here, we investigated covalent conjugation of a CPP to dextran in multiple copies and assessed the ability of resulted molecular hybrid to enter the cytoplasm of mammalian cells without largely compromising cell viability. As a CPP, we used a novel, low‐toxic cationic amphiphilic peptide L17E derived from M‐lycotoxin. Here, we show that cell‐penetrating properties of L17E are retained upon multivalent covalent linkage to dextran. Dextran‐L17E efficiently mediated cytoplasmic translocation of an attached functional peptide and a peptide nucleic acid (PNA). Moreover, a synthetic route was established to mask the lysine side chains of L17E with a photolabile protecting group thus opening avenues for light‐triggered activation of cellular uptake.

中文翻译：

多价葡聚糖杂合体用于生物分子货物的有效胞质递送

基于肽和蛋白质的新型生物治疗剂的开发通常仅限于细胞外靶标，因为这些分子无法到达细胞质。近年来，提出了几种方法来克服这种限制。大量的细胞穿透肽（CPPs）被开发用于细胞不可渗透的货物分子的细胞质递送。对于许多 CPP，支架上的多聚化或多拷贝排列可改善递送，但也具有更高的细胞毒性。最近，我们引入了葡聚糖作为多价亲水多糖支架，用于细胞靶向货物的多聚化。在这里，我们研究了 CPP 与多拷贝葡聚糖的共价缀合，并评估了所得分子杂交体进入哺乳动物细胞细胞质的能力，而不会在很大程度上损害细胞活力。作为 CPP，我们使用了一种源自 M-lycotoxin 的新型低毒阳离子两亲肽 L17E。在这里，我们表明 L17E 的细胞穿透特性在与葡聚糖的多价共价连接后得以保留。葡聚糖-L17E 有效介导附着的功能肽和肽核酸 (PNA) 的细胞质易位。此外，建立了一种合成路线，用光不稳定的保护基团掩盖 L17E 的赖氨酸侧链，从而为光触发激活细胞摄取开辟了道路。葡聚糖-L17E 有效介导附着的功能肽和肽核酸 (PNA) 的细胞质易位。此外，建立了一种合成路线，用光不稳定的保护基团掩盖 L17E 的赖氨酸侧链，从而为光触发激活细胞摄取开辟了道路。葡聚糖-L17E 有效介导附着的功能肽和肽核酸 (PNA) 的细胞质易位。此外，建立了一种合成路线，用光不稳定的保护基团掩盖 L17E 的赖氨酸侧链，从而为光触发激活细胞摄取开辟了道路。

更新日期：2021-03-03

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