Piggybacking on the Cholera Toxin: Identification of a CTB-Binding Protein as an Approach for Targeted Delivery of Proteins to Motor Neurons
Piggybacking on the Cholera Toxin: Identification of a CTB-Binding Protein as an Approach for Targeted Delivery of Proteins to Motor Neurons
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DOI：
10.1021/acs.bioconjchem.1c00373
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发表时间：
2021-09-27
影响因子：
4.7
通讯作者：
Turnbull, W. Bruce
中科院分区：
文献类型：
--
作者：
Balmforth, Matthew R.;Haigh, Jessica;Turnbull, W. Bruce
对于将生物药物如多肽或核酸递送至中枢神经系统以治疗和理解神经变性疾病存在显著的未满足的需求。天然存在的细菌毒素被认为是满足这一需求的工具。然而，由于将大分子药物与毒素连接的复杂性以及与大量重组毒素一起工作的固有危险，还没有成功地利用这种途径。开发一种方法，其中细菌毒素的无毒靶向亚基可以在体内给药前立即与药物组装，有可能避免其中的一些问题。使用噬菌体展示筛选，我们鉴定了两种抗体模拟物，抗霍乱毒素Affimer（ACTA）-A2和ACTA-C6，其与霍乱毒素B亚基的非结合面非共价缔合。在开发非病毒运动神经元药物递送载体的第一步中，我们表明Affimers可以选择性地递送到体内运动神经元。
A significant unmet need exists for the delivery of biologic drugs such as polypeptides or nucleic acids to the central nervous system for the treatment and understanding of neurodegenerative diseases. Naturally occurring bacterial toxins have been considered as tools to meet this need. However, due to the complexity of tethering macromolecular drugs to toxins and the inherent dangers of working with large quantities of recombinant toxins, no such route has been successfully exploited. Developing a method where a bacterial toxin's nontoxic targeting subunit can be assembled with a drug immediately prior to in vivo administration has the potential to circumvent some of these issues. Using a phage- display screen, we identified two antibody mimetics, anticholera toxin Affimer (ACTA)-A2 and ACTA-C6 that noncovalently associate with the nonbinding face of the cholera toxin B-subunit. In a first step toward the development of a nonviral motor neuron drug-delivery vehicle, we show that Affimers can be selectively delivered to motor neurons in vivo.