<i>De Novo</i> Design of Peptide Masks Enables Rapid Generation of Conditionally-Active Miniprotein Binders.

ABSTRACT: The widespread expression of therapeutic targets in both diseased and healthy tissues poses a major challenge for protein-based therapeutics, often leading to dose-limiting side effects. One promising strategy to enhance selectivity is reversible inactivation via affinity masks tethered through cleavable linkers responsive to disease-specific cues. Here, we introduce a workflow for the de novo design of peptide masks that reversibly inactivate miniprotein binders. By extending the C-terminus of the binder with a protease-cleavable linker and a masking helix, we generated minimal constructs that sterically block the receptor-binding interface. We applied this strategy to four therapeutically relevant targets, EGFR domains I and III, FGFR2, and IL7Rα, demonstrating broad applicability

SUBMITTER: Escobar-Rosales M 

PROVIDER: S-EPMC12703739 | biostudies-literature | 2025 Dec

REPOSITORIES: biostudies-literature