期刊
ADVANCED SCIENCE
卷 8, 期 11, 页码 -出版社
WILEY
DOI: 10.1002/advs.202003558
关键词
anti‐ hematogenous metastatic activities; polymer– peptidomimetic conjugates; protein– protein interactions; structure‐ based drug design
资金
- National Natural Science Foundation of China [81972886, 81903499, 21807071, 41729002]
- Innovative Research Team of High-Level Local Universities in Shanghai [SSMU-ZLCX20180702]
This study identifies a novel inhibitor of DR6/APP interaction as a promising anti-hematogenous metastatic agent, which exhibits strong binding potency and excellent pharmacokinetic properties. The compound efficiently protects vascular endothelial cells from necroptosis induced by tumor cells and demonstrates significant anti-hematogenous metastatic activity in multiple metastatic mouse models.
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 PEG(5k)) is obtained as the most promising agent with the strongest binding potency (K-D = 51.12 x 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.
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