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Updated: Jan 20, 2026

Biotinylated Cell-penetrating Peptides to Study Intracellular Protein-protein Interactions

Biotinylated Cell-penetrating Peptides to Study Intracellular Protein-protein Interactions

Published on: December 20, 2017

細胞内癌原遺伝子タンパク質を利用した細胞毒性タンパク質の放出

Matthias Schild¹, Dennis Gillingham¹

¹Department of Chemistry, University of Basel 4056 Basel Switzerland dennis.gillingham@unibas.ch.

RSC medicinal chemistry

|January 19, 2026

Abstract:

The success of antibody-drug conjugates has demonstrated the value of targeted delivery strategies for cytotoxic molecules. However, many oncogenic drivers remain inaccessible to antibodies due to their intracellular location, and these drivers are currently mainly addressed using small molecule inhibitors. This work explores repurposing such inhibitors for the intracellular delivery and controlled release of cytotoxic payloads. Using click-to-release chemistry, a pre-targeting strategy was developed where inhibitor-tetrazine conjugates enable selective activation of systemically administered trans-cyclooctene (TCO) caged prodrugs. This concept was demonstrated using the epidermal growth factor receptor (EGFR), a key therapeutic target in non-small cell lung cancer. An afatinib-tetrazine conjugate achieved sufficient intracellular retention in EGFR-overexpressing cells to enable toxicity recovery from a TCO-protected monomethyl auristatin E (MMAE) derivative. Successful intracellular targeting and controlled payload release establish a foundation for expanding the scope of targeted drug delivery to previously inaccessible oncogenic drivers.

キーワード:

細胞内薬物送達クリック・トゥ・リリース化学プロドラッグ EGFR 癌治療

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