Securing LYTAC with Logic-Identification System for Cancer Cell-Selective Membrane Protein Degradation,Small

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Securing LYTAC with Logic-Identification System for Cancer Cell-Selective Membrane Protein Degradation
Small ( IF 13.0 ) Pub Date : 2024-03-03 , DOI: 10.1002/smll.202310039
Yanyun Fang ₁ , Yue Zhang ₂ , Shiyi Bi ₁ , Bo Peng ₁ , Caixia Wang ₁ , Huangxian Ju ₁ , Ying Liu _{1,

3}

Affiliation

Lysosome-targeting chimera (LYTAC) links proteins of interest (POIs) with lysosome-targeting receptors (LTRs) to achieve membrane protein degradation, which is becoming a promising therapeutic modality. However, cancer cell-selective membrane protein degradation remains a big challenge considering expressions of POIs in both cancer cells and normal cells, as well as broad tissue distribution of LTRs. Here a logic-identification system is designed, termed Logic-TAC, based on cell membrane-guided DNA calculations to secure LYTAC selectively for cancer cells. Logic-TAC is designed as a duplex DNA structure, with both POI and LTR recognition regions sealed to avoid systematic toxicity during administration. MCF-7 and MCF-10A are chosen as sample cancer cell and normal cell respectively. As input 1 for logic-identification, membrane proteins EpCAM, which is highly expressed by MCF-7 but barely by MCF-10A, reacts with Logic-TAC to expose POI recognition region. As input 2 for logic-identification, Logic-TAC binds to POI, membrane protein MUC1, to expose LTR recognition region. As output, MUC1 is connected to LTR and degraded via lysosome pathway selectively for cancer cell MCF-7 with little side effect on normal cell MCF-10A. The logic-identification system also demonstrated satisfactory in vivo therapeutic results, indicating its promising potential in precise targeted therapy.

中文翻译：

利用逻辑识别系统确保 LYTAC 的安全，以实现癌细胞选择性膜蛋白降解

溶酶体靶向嵌合体 (LYTAC) 将目标蛋白 (POI) 与溶酶体靶向受体 (LTR) 连接起来，以实现膜蛋白降解，这正在成为一种有前途的治疗方式。然而，考虑到 POIs 在癌细胞和正常细胞中的表达以及 LTR 的广泛组织分布，癌细胞选择性膜蛋白降解仍然是一个巨大的挑战。这里设计了一个逻辑识别系统，称为 Logic-TAC，基于细胞膜引导的 DNA 计算，以确保 LYTAC 选择性地识别癌细胞。 Logic-TAC 被设计为双链 DNA 结构，POI 和 LTR 识别区域均被密封，以避免给药期间的系统毒性。分别选择MCF-7和MCF-10A作为样本癌细胞和正常细胞。作为逻辑识别的输入 1，膜蛋白 EpCAM 在 MCF-7 中高度表达，但在 MCF-10A 中几乎没有表达，与 Logic-TAC 反应以暴露 POI 识别区域。作为逻辑识别的输入 2，Logic-TAC 与 POI（膜蛋白 MUC1）结合，以暴露 LTR 识别区域。作为输出，MUC1与LTR连接，并通过溶酶体途径选择性地降解癌细胞MCF-7，对正常细胞MCF-10A几乎没有副作用。该逻辑识别系统也表现出了令人满意的体内治疗效果，表明其在精准靶向治疗方面的巨大潜力。

更新日期：2024-03-03

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