Integrin‐Targeting Knottin Peptide–Drug Conjugates Are Potent Inhibitors of Tumor Cell Proliferation

Abstract

Antibody-drug conjugates (ADCs) offer increased efficacy and reduced toxicity compared to systemic chemotherapy. Less attention has been paid to peptide-drug delivery, which has the potential for increased tumor penetration and facile synthesis. We report a knottin peptide-drug conjugate (KDC) and demonstrate that it can selectively deliver gemcitabine to malignant cells expressing tumor-associated integrins. This KDC binds to tumor cells with low-nanomolar affinity, is internalized by an integrin-mediated process, releases its payload intracellularly, and is a highly potent inhibitor of brain, breast, ovarian, and pancreatic cancer cell lines. Notably, these features enable this KDC to bypass a gemcitabine resistance mechanism found in pancreatic cancer cells. This work expands the therapeutic relevance of knottin peptides to include targeted drug delivery, and further motivates efforts to expand the drug-conjugate toolkit to include non-antibody protein scaffolds.

Beyond Antibodies as Binding Partners: The Role of Antibody Mimetics in Bioanalysis

“…Because knottins only consist of 30 amino acids, they can be generated chemically using peptide synthesizer, which avoids the cumbersome process of recombinant protein synthesis. Cox et al (146) incorporated 5-azido-L-norvaline into integrin-targeting knottin peptides using SPPS for gemcitabine conjugation. The knottin–gemcitabine conjugates show high antitumor effects compared to gemcitabine.…”

Neue Modalitäten für schwierige Zielstrukturen in der Wirkstoffentwicklung

“…[172] Konjugate von Peptiden mit niedermolekularen Verbindungen wurden jüngst vermehrt verwendet, um aktiv einen niedermolekularen oder Peptidwirkstoff zu einem spezifischen Gewebe oder Zelltyp zu transportieren. [178] Verschiedene Knottin-Gemcitabin-Konjugate mit Ester-, Carbamat-, Amid-und Abbildung 11. Beispielsweise wurde ein peptidischer Agonist gegen den GLP-1-Rezeptor (GLP-1R) mit Östrogen konjugiert, um das metabolische Syndrom zu adressieren (Abbildung 12 a).…”

Highly Constrained Bicyclic Scaffolds for the Discovery of Protease-Stable Peptides via mRNA Display

“…24, 25, 26 Knotted peptides and miniproteins have displayed a wide scope of biological activities, including uses as antimicrobials, 27, 28 protease inhibitors 29, 30 and as highly potent modulators of a variety of ion channels. 31, 32, 33 Furthermore, knotted peptides and peptide conjugates have been adapted for use as imaging agents 34, 35 and drug delivery vehicles 36 .…”