Mechanism of the blood-brain barrier modulation by cadherin peptides.

Exploration of drug science Pub Date : 2024-01-01 Epub Date: 2024-06-26 DOI:10.37349/eds.2024.00049
Elinaz Farokhi, Ahmed L Alaofi, Vivitri D Prasasty, Filia Stephanie, Marlyn D Laksitorini, Krzysztof Kuczera, Teruna J Siahaan
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Abstract

Aim: This study was aimed at finding the binding site on the human E-cadherin for Ala-Asp-Thr Cyclic 5 (ADTC5), ADTC7, and ADTC9 peptides as blood-brain barrier modulator (BBBM) for determining their mechanism of action in modulating the blood-brain barrier (BBB).

Methods: ADTC7 and ADTC9 were derivatives of ADTC5 where the Val6 residue in ADTC5 was replaced by Glu6 and Tyr6 residues, respectively. The binding properties of ADTC5, ADTC7, and ADTC9 to the extracellular-1 (EC1) domain of E-cadherin were evaluated using chemical shift perturbation (CSP) method in the two dimensional (2D) 1H-15N-heteronuclear single quantum coherence (HSQC) nuclear magnetic resonance (NMR) spectroscopy. Molecular docking experiments were used to determine the binding sites of these peptides to the EC1 domain of E-cadherin.

Results: This study indicates that ADTC5 has the highest binding affinity to the EC1 domain of E-cadherin compared to ADTC7 and ADTC9, suggesting the importance of the Val6 residue as shown in our previous in vitro study. All three peptides have a similar binding site at the hydrophobic binding pocket where the domain swapping occurs. ADTC5 has a higher overlapping binding site with ADTC7 than that of ADTC9. Binding of ADTC5 on the EC1 domain influences the conformation of the EC1 C-terminal tail.

Conclusions: These peptides bind the domain swapping region of the EC1 domain to inhibit the trans-cadherin interaction that creates intercellular junction modulation to increase the BBB paracellular porosity.

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粘连蛋白肽调节血脑屏障的机制。
目的:本研究旨在寻找作为血脑屏障调节剂(BBBM)的Ala-Asp-Thr Cyclic 5(ADTC5)、ADTC7和ADTC9多肽在人E-cadherin上的结合位点,以确定其调节血脑屏障(BBB)的作用机制:ADTC7和ADTC9是ADTC5的衍生物,ADTC5中的Val6残基分别被Glu6和Tyr6残基取代。在二维(2D)1H-15N-异核单量子相干(HSQC)核磁共振(NMR)光谱中使用化学位移扰动(CSP)方法评估了ADTC5、ADTC7和ADTC9与E-cadherin的胞外-1(EC1)结构域的结合特性。分子对接实验用于确定这些肽与 E-cadherin EC1 结构域的结合位点:这项研究表明,与 ADTC7 和 ADTC9 相比,ADTC5 与 E-cadherin EC1 结构域的结合亲和力最高,这表明 Val6 残基的重要性正如我们之前的体外研究所示。这三种肽在发生结构域交换的疏水结合袋上都有相似的结合位点。与 ADTC9 相比,ADTC5 与 ADTC7 的结合位点重叠度更高。ADTC5 与 EC1 结构域的结合会影响 EC1 C 端尾部的构象:这些肽结合了 EC1 结构域的结构域交换区,从而抑制了跨粘连蛋白的相互作用,这种相互作用产生了细胞间连接调节,从而增加了 BBB 的细胞旁孔隙率。
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