粘蛋白
MUC1号
蛋白酶
聚糖
癌细胞
化学
融合蛋白
生物
癌症
细胞生物学
癌症研究
生物化学
糖蛋白
重组DNA
基因
酶
遗传学
作者
Kayvon Pedram,D. Judy Shon,Gabrielle S. Tender,Natália Rodrigues Mantuano,Jason J. Northey,Kevin J. Metcalf,Simon 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
标识
DOI:10.1038/s41587-023-01840-6
摘要
Abstract 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.
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