Elucidation and structural modeling of CD71 as a molecular target for cell-specific aptamer binding,Journal of the American Chemical Society

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Elucidation and structural modeling of CD71 as a molecular target for cell-specific aptamer binding
Journal of the American Chemical Society ( IF 14.4 ) Pub Date : 2019-06-11 , DOI: 10.1021/jacs.9b03720
Xiaoqiu Wu ₁ , Honglin Liu _{1,

2} , Dongmei Han ₁ , Bo Peng ₁ , Hui Zhang ₁ , Lin Zhang ₁ , Jianglin Li ₁ , Jing Liu , Cheng Cui _{1,

3} , Senbiao Fang , Min Li , Mao Ye ₁ , Weihong Tan _{1,

3,

4}

Affiliation

Pancreatic cancer is a highly lethal malignancy associated with tissues of the pancreas. Early diagnosis and effective treatment are crucial to improving the survival rate of patients with pancreatic cancer. In a previous study, we employed the cell-SELEX strategy to obtain an ssDNA aptamer termed XQ-2d with high binding affinity for pancreatic cancer. Here, we first identify CD71 as the XQ-2d-binding target. We found that knockdown of CD71 abolished the binding of XQ-2d and that the binding affinity of XQ-2d is associated with membrane-bound CD71, rather than total CD71 levels. Competitive analysis revealed that XQ-2d shares the same binding site on CD71 with transferrin (Tf), but not anti-CD71 antibody. We then used a surface energy transfer (SET) nanoruler to measure the distance between the binding sites of XQ-2d and anti-CD71 antibody, and it was about 15 nm. Furthermore, we did molecular dynamics simulation to clarify that the spatial structure of XQ-2d and Tf competitively binding to CD71. We also engi-neered XQ-2d-mediated targeted therapy for pancreatic cancer, using an XQ-2d-based complex for loading doxorubicin (Dox). Since CD71 is overexpressed not only in pancreatic cancer but also in a variety of tumors, our work provides a systematic novel way of studying a potential biomarker and also promising tools for cancer diagnosis and therapy, opening new doors for effective cancer theranostics.

中文翻译：

CD71 作为细胞特异性适体结合的分子靶标的阐明和结构建模

胰腺癌是一种与胰腺组织相关的高度致命的恶性肿瘤。早期诊断和有效治疗对于提高胰腺癌患者的生存率至关重要。在之前的一项研究中，我们采用细胞-SELEX 策略来获得称为 XQ-2d 的 ssDNA 适体，其对胰腺癌具有高结合亲和力。在这里，我们首先将 CD71 确定为 XQ-2d 结合目标。我们发现 CD71 的敲低消除了 XQ-2d 的结合，并且 XQ-2d 的结合亲和力与膜结合 CD71 相关，而不是与总 CD71 水平相关。竞争分析显示 XQ-2d 与转铁蛋白 (Tf) 共享 CD71 上相同的结合位点，但不与抗 CD71 抗体共享。然后我们使用表面能转移 (SET) 纳米尺来测量 XQ-2d 和抗 CD71 抗体结合位点之间的距离，它大约是 15 nm。此外，我们进行了分子动力学模拟以阐明 XQ-2d 和 Tf 的空间结构与 CD71 竞争性结合。我们还设计了 XQ-2d 介导的胰腺癌靶向治疗，使用基于 XQ-2d 的复合物加载阿霉素 (Dox)。由于 CD71 不仅在胰腺癌中过表达，而且在各种肿瘤中也过表达，我们的工作提供了一种研究潜在生物标志物的系统性新方法，也为癌症诊断和治疗提供了有前途的工具，为有效的癌症治疗学打开了新的大门。

更新日期：2019-06-11

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