School of Chemistry, School of Biomedical Sciences and Astbury Centre for Structural and Molecular Biology, University of Leeds, Leeds LS2 9JT, U.K.
School of Chemistry and Astbury Centre for Structural and Molecular Biology, University of Leeds, Leeds LS2 9JT, U.K.
Bioconjug Chem. 2021 Oct 20;32(10):2205-2212. doi: 10.1021/acs.bioconjchem.1c00373. Epub 2021 Sep 26.
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.
对于将生物药物（如多肽或核酸）递送到中枢神经系统以治疗和了解神经退行性疾病，存在着巨大的未满足的需求。天然存在的细菌毒素已被视为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处理大量重组毒素的固有危险，这种方法尚未成功利用。开发一种方法，使细菌毒素的无毒靶向亚基能够在体内给药前与药物立即组装，有可能规避其中的一些问题。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，它们与霍乱毒素 B 亚基的非结合面非共价结合。作为开发非病毒运动神经元药物递送载体的第一步，我们表明 Affimers 可以选择性地递送到体内的运动神经元。
