A novel LRP1-binding peptide L57 that crosses the blood brain barrier.
A novel LRP1-binding peptide L57 that crosses the blood brain barrier.
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DOI：
10.1016/j.bbrep.2017.07.003
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发表时间：
2017-12
影响因子：
2.7
通讯作者：
Ohtaki T
中科院分区：
文献类型：
--
作者：
Sakamoto K;Shinohara T;Adachi Y;Asami T;Ohtaki T
血脑屏障（BBB）是药物递送到中枢神经系统（CNS）中的主要障碍，特别是对于大分子如肽和蛋白质。然而，某些大分子可以通过受体介导的转胞吞（RMT）途径到达CNS，低密度脂蛋白受体相关蛋白1（LRP 1）是RMT的有前途的受体之一。据报道，LRP 1配体肽Angiopep-2可穿过BBB并将共价结合的药物递送到CNS中。虽然LRP 1配体与药物的缀合将是药物递送至CNS的有效方法，但迄今为止还没有报道其他可靠的LRP 1配体。在这项研究中，我们的目的是确定新的LRP 1配体，以进一步研究LRP 1介导的RMT。利用噬菌体展示技术，我们获得了一种新的肽，L57（TWPKHFDKHTFYSILKLGKH-OH），与LRP 1的簇4（Ser 3332-Asp 3779）结合的EC 50值为45 nM。L57在小鼠血浆中稳定长达20分钟。在小鼠中的原位脑灌注测定揭示了L57的显著高的BBB渗透性。总之，我们发现了L57，第一个具有BBB通透性的人工LRP 1结合肽。我们的研究结果将有助于RMT为基础的药物治疗中枢神经系统疾病的发展。通过噬菌体展示发现了第一个人工合成的LRP 1结合肽L57。L57结合LRP 1的胞外结构域，EC 50结合值为24 nM。L57在小鼠原位脑灌注和静脉注射中表现出脑摄取。
The blood-brain barrier (BBB) is a major obstacle to drug delivery into the central nervous system (CNS), in particular for macromolecules such as peptides and proteins. However, certain macromolecules can reach the CNS via a receptor-mediated transcytosis (RMT) pathway, and low-density lipoprotein receptor-related protein 1 (LRP1) is one of the promising receptors for RMT. An LRP1 ligand peptide, Angiopep-2, was reported to pass through the BBB and deliver covalently conjugated drugs into the CNS. While conjugation of LRP1 ligands with drugs would be an effective approach for drug delivery to the CNS, no other reliable LRP1 ligands have been reported to date. In this study, we aimed to identify novel LRP1 ligands to further investigate LRP1-mediated RMT. Using phage display technology, we obtained a novel peptide, L57 (TWPKHFDKHTFYSILKLGKH-OH), with an EC50 value of 45 nM for binding to cluster 4 (Ser3332–Asp3779) of LRP1. L57 was stable in mouse plasma for up to 20 min. In situ brain perfusion assay in mice revealed the significantly high BBB permeability of L57. In conclusion, we discovered L57, the first artificial LRP1-binding peptide with BBB permeability. Our findings will contribute to the development of RMT-based drugs for the treatment of CNS diseases. The first artificial LRP1-binding peptide L57 was discovered by phage display. L57 binds the extracellular domain of LRP1 with an EC50 binding value of 24 nM. L57 exhibits brain uptake in in situ brain perfusion and i.v. injection in mice.