Design of a mucin-selective protease for targeted degradation of cancer-associated mucins.
Nat Biotechnol
; 42(4): 597-607, 2024 Apr.
Article
en En
| MEDLINE
| ID: mdl-37537499
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.
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Mucinas
/
Neoplasias
Tipo de estudio:
Risk_factors_studies
Límite:
Animals
Idioma:
En
Año:
2024
Tipo del documento:
Article