多肽脑靶向的分子决定因素:通过实验验证的荟萃分析方法。

IF 5.9 1区 医学 Q1 NEUROSCIENCES
Marco Cavaco, Patrícia Fraga, Javier Valle, Ruben D M Silva, Lurdes Gano, João D G Correia, David Andreu, Miguel A R B Castanho, Vera Neves
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引用次数: 0

摘要

血脑屏障(BBB)多肽封闭剂(BBBpS)能够穿过 BBB 到达大脑。尽管脑靶向药物在药理学中非常重要,但 BBBpS 的特性却不甚明了。目前,它们的开发依赖于一种经验性假设,即细胞穿透肽(CPPs)已被证实具有穿越脂质膜的能力,同样也能起到 BBBpS 的作用。CPPs/BBBpS 之间的关系仍然难以捉摸,而且据我们所知,迄今为止还没有进行过彻底的实验研究。在这项工作中,我们确定/量化了 BBBpS 的主要物理化学特性,然后寻找具有这些特性的 CPPs,从而寻找潜在的 BBBpS。我们发现 BBBpS 的具体特征包括(i) 体积小;(ii) 没有或只有少量芳香残基;(iii) 疏水性;(iv) 轻微的阳离子性质。然后,我们通过普通最小二乘法分析选出了得分最高的 10 个分子,并对它们进行了体外和体内测试。总之,我们确定了多肽脑靶向的分子决定因素,设计了一种可用于从氨基酸残基序列辅助设计具有潜在脑穿透能力的多肽的方法,并在 CPP 库中发现了四种新的 BBBpS。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Molecular determinants for brain targeting by peptides: a meta-analysis approach with experimental validation.

Blood-brain barrier (BBB) peptide-shuttles (BBBpS) are able to translocate the BBB and reach the brain. Despite the importance of brain targeting in pharmacology, BBBpS are poorly characterized. Currently, their development relies on the empiric assumption that cell-penetrating peptides (CPPs), with proven ability to traverse lipid membranes, will likewise behave as a BBBpS. The relationship between CPPs/BBBpS remains elusive and, to the best of our knowledge, has not hitherto been subject to thorough experimental scrutiny. In this work, we have identified/quantified the main physicochemical properties of BBBpS and then searched for CPPs with these properties, hence potential BBBpS. The specific features found for BBBpS are: (i) small size, (ii) none or few aromatic residues, (iii) hydrophobic, and (iv) slight cationic nature. Then, we selected the 10 scoring best in an ordinary least squares analysis, and tested them in vitro and in vivo. Overall, we identified the molecular determinants for brain targeting by peptides, devised a methodology that can be used to assist in the design of peptides with potential brain penetration from amino acid residue sequences, and found four new BBBpS within the CPP library.

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来源期刊
Fluids and Barriers of the CNS
Fluids and Barriers of the CNS Neuroscience-Developmental Neuroscience
CiteScore
10.70
自引率
8.20%
发文量
94
审稿时长
14 weeks
期刊介绍: "Fluids and Barriers of the CNS" is a scholarly open access journal that specializes in the intricate world of the central nervous system's fluids and barriers, which are pivotal for the health and well-being of the human body. This journal is a peer-reviewed platform that welcomes research manuscripts exploring the full spectrum of CNS fluids and barriers, with a particular focus on their roles in both health and disease. At the heart of this journal's interest is the cerebrospinal fluid (CSF), a vital fluid that circulates within the brain and spinal cord, playing a multifaceted role in the normal functioning of the brain and in various neurological conditions. The journal delves into the composition, circulation, and absorption of CSF, as well as its relationship with the parenchymal interstitial fluid and the neurovascular unit at the blood-brain barrier (BBB).
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