Smart cell-specific protein therapeutics for head and neck cancer.
Smart cell-specific protein therapeutics for head and neck cancer.
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针对头颈癌的智能细胞特异性蛋白质疗法。
DOI：
10.1111/odi.13203
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发表时间：
2020
期刊：
影响因子：
3.8
通讯作者：
Sunavala-Dossabhoy,Gulshan
中科院分区：
文献类型：
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作者：
Sunavala-Dossabhoy,Gulshan
与基因治疗载体相比，直接传递蛋白质是一种更安全的选择，因为可以实现快速、稳健和短期的蛋白质表达，而不会伴随插入突变的风险。细胞穿透性多肽(CPPs)是一类从病毒蛋白中提取或人工合成的多肽。这些多肽在体外和体内都可以很容易地转移到活细胞中，当它们与蛋白质融合时，它们是蛋白质内化和细胞内蛋白质水平调控的宝贵工具。富含精氨酸和赖氨酸残基的HIV TAT转导多肽(47-57aa)因其优越的跨细胞膜转运能力而得到广泛应用。阳离子多肽靠近带负电荷的细胞膜会导致细胞膜变形和细胞骨架重塑，从而促进巨噬细胞吞噬作用在细胞内摄取附着的生物大分子(Mishra等，2010)。然而，CPP融合蛋白的细胞进入不是细胞特异性的(图1A)，靶向递送仍然是一个主要挑战。在蛋白质递送中改造细胞特异性可以极大地减少非靶向细胞中的有害影响。人类TLK1在染色质重塑、细胞周期调节和基因组断裂修复中发挥作用(Sunavala-Dossabhoy等人，2018年)。先发制人地将TAT-TLK1融合蛋白输送到培养中的唾液细胞或体内的唾液腺，被证明可以防止与辐射相关的细胞活性和功能丧失(Sunavala-Dossabhoy等人，2012年)。在试图提高治疗安全性，特别是在癌症护理的背景下，Nair等人(2019)定制了蛋白质以感知生物信号并实现细胞选择性蛋白质转导。大多数头颈癌都大量表达基质金属蛋白酶(MMPs)(Rosenthal和Matrisian 2006)。因此，生物化学的基本原理是在TAT肽和TLK1蛋白之间引入一种对MMPs敏感的多肽连接物(MS)，从而使细胞外的裂解反应于肿瘤环境中的MMPs的病理水平而减少TLK1进入癌细胞。分子靶向策略实现了蛋白质专门输送到健康细胞(图1B)。
Direct protein delivery is a safer alternative to gene therapy vectors as rapid, robust, and short-term protein expression can be achieved without the accompanying risk of insertional mutagenesis. Cell-penetrating peptides (CPPs) are a diverse class of peptides that have been derived from viral proteins or developed synthetically. These peptides can readily translocate into live cells in vitro and in vivo, and when fused to proteins, they are an invaluable tool for protein internalization and manipulation of intracellular protein levels. The arginine and lysine residue-rich HIV TAT transduction peptide (47–57 aa) has been widely used because of its superior ability to delivery a variety of payloads across the cell membranes. Close proximity of the cationic peptide to the negatively-charged cell membrane induces membrane deformation and cytoskeletal remodeling, which facilitates intracellular uptake of attached biological macromolecules by macropinocytosis (Mishra et al., 2010). Cellular entry of CPP-fusion proteins however, is not cell-specific (Figure 1A), and targeted delivery remains a major challenge. Engineering cell-specificity in protein delivery can greatly minimize the unwanted effects in non-targeted cells.Human Tousled-like kinase 1 (TLK1) functions in chromatin remodeling, regulation of cell cycle and repair of genomic breaks (Sunavala-Dossabhoy et al., 2018). Preemptive delivery of TAT-TLK1 fusion protein to salivary cells in culture or salivary glands in vivo was shown to prevent radiation-associated loss of cell viability and function (Sunavala-Dossabhoy et al., 2012). In an attempt to improve therapeutic safety especially, in context of cancer care, Nair et al.(2019) tailored the protein to sense biological signals and achieve cell-selective protein transduction. A majority of head and neck cancers express matrix-metalloproteinases (MMP) in abundance (Rosenthal and Matrisian 2006) The biochemical rationale was, therefore, to introduce a MMP-sensitive peptide linker (MS) between TAT peptide and TLK1 protein such that extracellular cleavage in response to pathological levels of MMP in the cancer environment curtails TLK1 entry in cancer cells. The molecular targeting strategy achieves protein delivery specifically to healthy cells (Figure 1B).