Multi-Arm PEG/Peptidomimetic Conjugate Inhibitors of DR6/APP Interaction Block Hematogenous Tumor Cell Extravasation.

Abstract

The binding of amyloid precursor protein (APP) expressed on tumor cells to death receptor 6 (DR6) could initiate the necroptosis pathway, which leads to necroptotic cell death of vascular endothelial cells (ECs) and results in tumor cells (TCs) extravasation and metastasis. This study reports the first inhibitor of DR6/APP interaction as a novel class of anti-hematogenous metastatic agent. By rationally utilizing three combined strategies including selection based on phage display library, d-retro-inverso modification, and multiple conjugation of screened peptidomimetic with 4-arm PEG, the polymer-peptidomimetic conjugate PEG-tAHP-DRI (tetra-(D-retro-inverso isomer of AHP-12) substitued 4-arm PEG5k ) is obtained as the most promising agent with the strongest binding potency (KD  = 51.12 × 10-9  m) and excellent pharmacokinetic properties. Importantly, PEG-tAHP-DRI provides efficient protection against TC-induced ECs necroptosis both in vitro and in vivo. Moreover, this ligand exhibits prominent anti-hematogenous metastatic activity in serval different metastatic mouse models (B16F10, 4T1, CT26, and spontaneous lung metastasis of 4T1 orthotopic tumor model) and displays no apparent detrimental effects in preliminary safety evaluation. Collectively, this study demonstrates the feasibility of exploiting DR6/APP interaction to regulate hematogenous tumor cells transendothelial migration and provides PEG-tAHP-DRI as a novel and promising inhibitor of DR6/APP interaction for developments of anti-hematogenous metastatic therapies.

• Authors: Liting Wang, Qing Shen, Hongze Liao, Hao Fu, Qi Wang, Jian Yu, Wei Zhang, Chuanrong Chen, Yang Dong, Xupeng Yang, Qianqian Guo, Jiali Zhang, Jian Zhang, Wei Zhang, Houwen Lin, Yourong Duan
• Journal: Advanced science (Weinheim, Baden-Wurttemberg, Germany) (Adv Sci (Weinh)) Vol. 8 Issue 11 Pg. e2003558 (06 2021) ISSN: 2198-3844 [Electronic] Germany
• PMID: 34105277 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021 The Authors. Advanced Science published by Wiley-VCH GmbH.

Chemical References

• Amyloid beta-Protein Precursor
• Ligands
• Peptidomimetics
• Receptors, Tumor Necrosis Factor
• TNFRSF21 protein, human

Topics

• Amyloid beta-Protein Precursor (antagonists & inhibitors, genetics)
• Animals
• Cell Communication (drug effects)
• Disease Models, Animal
• Endothelial Cells (drug effects, pathology)
• Hematologic Neoplasms (blood, drug therapy, genetics, pathology)
• Humans
• Ligands
• Melanoma, Experimental (drug therapy, genetics, pathology)
• Mice
• Neoplasm Metastasis
• Peptidomimetics (chemistry, pharmacology)
• Receptors, Tumor Necrosis Factor (antagonists & inhibitors, genetics)
• Transendothelial and Transepithelial Migration (drug effects, genetics)