The blood–brain barrier (BBB) hampers the delivery of therapeutic proteins into the brain. BBB-shuttle peptides have been conjugated to therapeutic payloads to increase the permeability of these molecules. However, most BBB-shuttles have several limitations, such as a lack of resistance to proteases and low effectiveness in transporting large biomolecules. We have previously reported on the THRre peptide as a protease-resistant BBB-shuttle that is able to increase the transport of fluorophores and quantum dots in vivo. In this work, we have evaluated the capacity of linear and branched THRre to increase the permeability of proteins in cellular models of the BBB. With this purpose, we have covalently attached peptides with one or two copies of the BBB-shuttle to proteins in order to develop chemically well-defined peptide–protein conjugates. While THRre does not enhance the uptake and transport of a model protein in BBB cellular models, branched THRre peptides displaying two copies of the BBB-shuttle result in a 2.6-fold increase.

中文翻译：

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支链 BBB 穿梭肽：化学选择性修饰蛋白质以增强血脑屏障转运†

血脑屏障 (BBB) 阻碍治疗性蛋白质输送到大脑中。BBB-穿梭肽已与治疗有效负载缀合，以增加这些分子的渗透性。然而，大多数 BBB 穿梭机有一些局限性，例如缺乏蛋白酶抗性以及运输大生物分子的效率较低。我们之前曾报道过 THRre 肽作为一种蛋白酶抗性 BBB 穿梭机，能够增加体内荧光团和量子点的运输。在这项工作中，我们评估了线性和分支 THRre 增加 BBB 细胞模型中蛋白质通透性的能力。为此，我们将带有一个或两个 BBB 穿梭拷贝的肽共价连接到蛋白质上，以开发化学结构明确的肽-蛋白质缀合物。虽然 THRre 不会增强 BBB 细胞模型中模型蛋白的摄取和转运，但展示两个 BBB 穿梭副本的分支 THRre 肽会导致 2.6 倍的增加。