Multi‐Arm PEG/Peptidomimetic Conjugate Inhibitors of DR6/APP Interaction Block Hematogenous Tumor Cell Extravasation. Issue 11 (18th March 2021)

• Record Type: Journal Article
• Authors: Wang, Liting; Shen, Qing; Liao, Hongze; Fu, Hao; Wang, Qi; Yu, Jian; Zhang, Wei; Chen, Chuanrong; Dong, Yang; Yang, Xupeng; Guo, Qianqian; Zhang, Jiali; Zhang, Jian; Zhang, Wei; Lin, Houwen; Duan, Yourong
• Is Part Of: Advanced science. Volume 8:Issue 11(2021)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2021-03-18
• Subjects: anti‐hematogenous metastatic activities -- polymer–peptidomimetic conjugates -- protein–protein interactions -- structure‐based drug design; Science -- Periodicals; 505
• DOI: 10.1002/advs.202003558
• Languages: English
• ISSNs: 2198-3844

Abstract

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 ( K D = 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. Abstract : Binding of amyloid precursor protein (APP) and death receptor 6 (DR6) is shown to initiate the necroptosis pathway and lead to tumor cells metastasis. The combined strategies of selection based on phage display library, d ‐retro‐inverso modification, and multiple conjugation result in the development of conjugate PEG‐tAHP‐DRI (tetra‐(D‐retro‐inverso isomer of AHP‐12) substitued 4‐arm PEG5k ) that blocks APP‐DR6 interactions and shows promising anti‐hematogenous metastatic activity both in vitro and in vivo.