针对癌相关粘液蛋白的靶向降解设计了一种黏膜选择性蛋白酶。
Design of a mucin-selective protease for targeted degradation of cancer-associated mucins.
发表日期：2023 Aug 03
作者：
Kayvon Pedram, D Judy Shon, Gabrielle S Tender, Natalia R Mantuano, Jason J Northey, Kevin J Metcalf, Simon P Wisnovsky, Nicholas M Riley, Giovanni C Forcina, Stacy A Malaker, Angel Kuo, Benson M George, Caitlyn L Miller, Kerriann M Casey, José G Vilches-Moure, Michael J Ferracane, Valerie M Weaver, Heinz Läubli, Carolyn R Bertozzi
来源：
BIOMEDICINE & PHARMACOTHERAPY
摘要：
靶向蛋白质降解是一种新兴的策略，用于消除经典的难以靶向的蛋白质。在这里，为了扩大可靶向底物的范围，我们设计了通过识别离散肽和糖基模体实现底物选择性，并通过抗原驱动的细胞表面结合实现细胞类型选择性的降解剂。我们将这种方法应用于粘蛋白，即通过生物物理和免疫机制推动癌症进程的O-糖基化蛋白质。通过对细菌粘蛋白选择性蛋白酶的工程改造，获得了一个用于与肿瘤抗原结合的纳米抗体融合的变异体。由此得到的结合物能选择性降解癌细胞上的粘蛋白，在粘蛋白驱动的生长和存活的培养模型中促进细胞死亡，并在乳腺癌进展的小鼠模型中减小肿瘤生长。这项工作为开发能够降解目标细胞上特定蛋白质糖基型的生物制剂奠定了基础。© 2023. 作者(s)。
Targeted protein degradation is an emerging strategy for the elimination of classically undruggable proteins. Here, to expand the landscape of targetable substrates, we designed degraders that achieve substrate selectivity via recognition of a discrete peptide and glycan motif and achieve cell-type selectivity via antigen-driven cell-surface binding. We applied this approach to mucins, O-glycosylated proteins that drive cancer progression through biophysical and immunological mechanisms. Engineering of a bacterial mucin-selective protease yielded a variant for fusion to a cancer antigen-binding nanobody. The resulting conjugate selectively degraded mucins on cancer cells, promoted cell death in culture models of mucin-driven growth and survival, and reduced tumor growth in mouse models of breast cancer progression. This work establishes a blueprint for the development of biologics that degrade specific protein glycoforms on target cells.© 2023. The Author(s).