MiniAp-4: A Venom-Inspired Peptidomimetic for Brain Delivery.
MiniAp-4: A Venom-Inspired Peptidomimetic for Brain Delivery.
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DOI：
10.1002/anie.201508445
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发表时间：
2016-01-11
期刊：
影响因子：
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通讯作者：
Teixidó M
中科院分区：
文献类型：
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作者：
Oller-Salvia B;Sánchez-Navarro M;Ciudad S;Guiu M;Arranz-Gibert P;Garcia C;Gomis RR;Cecchelli R;García J;Giralt E;Teixidó M
跨血脑屏障（BBB）的药物递送对于靶向中枢神经系统的治疗是一个巨大的挑战。尽管BBB穿梭肽非侵入性地增强了向脑中的转运，但它们的应用部分地受到对蛋白酶的不稳定性的限制。本研究提出使用来自毒液的环肽作为一种负担得起的方法来规避这一缺点。蜂毒蛋白是一种来自蜂毒的神经毒素，通过降低其复杂性、毒性和免疫原性，同时保留脑靶向、主动转运和蛋白酶抗性，使其最小化。在所设计的类似物中，单环内酰胺桥接的肽模拟物MiniAp-4是最具渗透性的。该分子能够在基于人细胞的BBB模型中转运蛋白质和纳米颗粒。此外，MiniAp-4可以有效地将货物穿过BBB输送到小鼠的脑实质中。
Drug delivery across the blood–brain barrier (BBB) is a formidable challenge for therapies targeting the central nervous system. Although BBB shuttle peptides enhance transport into the brain non‐invasively, their application is partly limited by lability to proteases. The present study proposes the use of cyclic peptides derived from venoms as an affordable way to circumvent this drawback. Apamin, a neurotoxin from bee venom, was minimized by reducing its complexity, toxicity, and immunogenicity, while preserving brain targeting, active transport, and protease resistance. Among the analogues designed, the monocyclic lactam‐bridged peptidomimetic MiniAp‐4 was the most permeable. This molecule is capable of translocating proteins and nanoparticles in a human‐cell‐based BBB model. Furthermore, MiniAp‐4 can efficiently deliver a cargo across the BBB into the brain parenchyma of mice.