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The combination of amyloid precursor protein (APP) expressed on iNature tumor cells and death receptor 6 (DR6) can initiate the programmed cell necrosis pathway, which leads to programmed cell necrosis of vascular endothelial cells (ECs) and leads to tumor cells (TCs) Extravasation and metastasis.
On March 18, 2021, Duan Yourong, Lin Houwen and Liao Hongze from Shanghai Jiaotong University published an online report entitled "Multi-Arm PEG/Peptidomimetic Conjugate Inhibitors of DR6/APP Interaction Block Hematogenous Tumor Cell Extravasation" in Advanced Science (IF=16) Research paper, this research reports the first inhibitor of DR6/APP interaction, which is a new type of anti-blood metastasis agent.
Through rational use of three combination strategies, including selection based on phage display library, d-reverse modification and multiple conjugation of selected peptidomimetics and 4-arm PEG, polymer-peptidomimetic conjugate PEG-tAHP-DRI has the most The most promising drug with strong binding power and excellent pharmacokinetic properties obtained the retroisomer of AHP-12 (replaced by 4-arm PEG5k).
Importantly, PEG-tAHP-DRI can effectively resist TC-induced EC necrosis in vitro and in vivo.
In addition, the ligand has shown significant anti-hematogenous metastasis activity in several different metastatic mouse models (B16F10, 4T1, CT26 and 4T1 orthotopic tumor models of spontaneous lung metastasis), and has not been evaluated in the preliminary safety evaluation.
Show any obvious harmful effects.This study generally demonstrates the feasibility of using DR6/APP interaction to regulate transendothelial migration of blood-borne tumor cells, and provides PEG-tAHP-DRI as a DR6/APP interaction for the development of anti-blood-borne metastasis therapies A novel and promising inhibitor.
Preventing tumor metastasis is one of the main goals in the treatment of many cancers.
Extremely complex processes and molecular mechanisms have led to unsatisfactory progress in this field.
Recently, it has been reported for the first time that tumor cells (TCs) in the blood system induce necroptosis of vascular endothelial cells (ECs), which promotes the extravasation and metastasis of TCs.
Therefore, blocking the programmed cell necrosis pathway may be a potential method to prevent tumor blood-borne metastasis.
So far, most research in this field has focused on the development of receptor-interacting protein kinase 1 (RIPK1) inhibitors, which is a key multifunctional protein involved in the regulation of programmed cell necrosis, but many known RIPK1 inhibitors The drug is not suitable for clinical research due to its unsatisfactory pharmacokinetic properties or side effects.
In addition, the combination of amyloid precursor protein (APP) and death receptor 6 (DR6) relieves the positive regulation of the programmed cell necrosis pathway, while knocking down APP or DR6 leads to TC-induced programmed cell necrosis and TCs across Endothelial migration.
These studies show that the interaction between APP and DR6 provides a new target for anti-blood metastasis therapy.
DR6 is widely expressed in a variety of cells including neuronal cells and endothelial cells, and is widely known for being associated with normal cell body death and axon pruning.
Its extracellular domain consists of four cysteine-rich domain (CRD) modules, followed by a transmembrane domain and a cytoplasmic death domain.
DR6 expressed on the surface of ECs can be activated by APP, which then initiates the necrosis process of ECs.
There is no report on inhibitors of DR6/APP interaction, and there is still an urgent need for highly effective inhibitors.
In this study, the first class of DR6/APP interaction inhibitors was provided.
First, a structure-based drug design using a random heptapeptide phage display library was used to obtain 24 peptides with good affinity for DR6, and then the structure of these peptides was optimized by d-reverse modification to provide a stronger binding force.
Kind of peptidomimetics and better pharmacokinetic characteristics.
In addition, by combining multi-arm polymers with the selected peptidomimetics, conjugated PEG-tAHP-DRI becomes the most effective inhibitor, which not only shows the strongest affinity for the target, but also has a satisfactory serum half-life .
Due to its high binding affinity to DR6 and long-term effects on the circulatory system, the conjugated inhibitor shows excellent anti-blood metastasis effects in vitro and in vivo.
In addition, PEG-tAHP-DRI has no obvious toxicity and harmful effects on the heart, liver and kidney, and is naturally inert to DR6-related signal transduction pathways, which provides enlightenment for the safe clinical application of PEG-tAHP-DRI.
In summary, this study provides a promising polymer coupling agent targeting DR6 for future anti-blood metastasis therapies.
Reference message: https://onlinelibrary.
wiley.
com/doi/10.
1002/advs.
202003558
On March 18, 2021, Duan Yourong, Lin Houwen and Liao Hongze from Shanghai Jiaotong University published an online report entitled "Multi-Arm PEG/Peptidomimetic Conjugate Inhibitors of DR6/APP Interaction Block Hematogenous Tumor Cell Extravasation" in Advanced Science (IF=16) Research paper, this research reports the first inhibitor of DR6/APP interaction, which is a new type of anti-blood metastasis agent.
Through rational use of three combination strategies, including selection based on phage display library, d-reverse modification and multiple conjugation of selected peptidomimetics and 4-arm PEG, polymer-peptidomimetic conjugate PEG-tAHP-DRI has the most The most promising drug with strong binding power and excellent pharmacokinetic properties obtained the retroisomer of AHP-12 (replaced by 4-arm PEG5k).
Importantly, PEG-tAHP-DRI can effectively resist TC-induced EC necrosis in vitro and in vivo.
In addition, the ligand has shown significant anti-hematogenous metastasis activity in several different metastatic mouse models (B16F10, 4T1, CT26 and 4T1 orthotopic tumor models of spontaneous lung metastasis), and has not been evaluated in the preliminary safety evaluation.
Show any obvious harmful effects.This study generally demonstrates the feasibility of using DR6/APP interaction to regulate transendothelial migration of blood-borne tumor cells, and provides PEG-tAHP-DRI as a DR6/APP interaction for the development of anti-blood-borne metastasis therapies A novel and promising inhibitor.
Preventing tumor metastasis is one of the main goals in the treatment of many cancers.
Extremely complex processes and molecular mechanisms have led to unsatisfactory progress in this field.
Recently, it has been reported for the first time that tumor cells (TCs) in the blood system induce necroptosis of vascular endothelial cells (ECs), which promotes the extravasation and metastasis of TCs.
Therefore, blocking the programmed cell necrosis pathway may be a potential method to prevent tumor blood-borne metastasis.
So far, most research in this field has focused on the development of receptor-interacting protein kinase 1 (RIPK1) inhibitors, which is a key multifunctional protein involved in the regulation of programmed cell necrosis, but many known RIPK1 inhibitors The drug is not suitable for clinical research due to its unsatisfactory pharmacokinetic properties or side effects.
In addition, the combination of amyloid precursor protein (APP) and death receptor 6 (DR6) relieves the positive regulation of the programmed cell necrosis pathway, while knocking down APP or DR6 leads to TC-induced programmed cell necrosis and TCs across Endothelial migration.
These studies show that the interaction between APP and DR6 provides a new target for anti-blood metastasis therapy.
DR6 is widely expressed in a variety of cells including neuronal cells and endothelial cells, and is widely known for being associated with normal cell body death and axon pruning.
Its extracellular domain consists of four cysteine-rich domain (CRD) modules, followed by a transmembrane domain and a cytoplasmic death domain.
DR6 expressed on the surface of ECs can be activated by APP, which then initiates the necrosis process of ECs.
There is no report on inhibitors of DR6/APP interaction, and there is still an urgent need for highly effective inhibitors.
In this study, the first class of DR6/APP interaction inhibitors was provided.
First, a structure-based drug design using a random heptapeptide phage display library was used to obtain 24 peptides with good affinity for DR6, and then the structure of these peptides was optimized by d-reverse modification to provide a stronger binding force.
Kind of peptidomimetics and better pharmacokinetic characteristics.
In addition, by combining multi-arm polymers with the selected peptidomimetics, conjugated PEG-tAHP-DRI becomes the most effective inhibitor, which not only shows the strongest affinity for the target, but also has a satisfactory serum half-life .
Due to its high binding affinity to DR6 and long-term effects on the circulatory system, the conjugated inhibitor shows excellent anti-blood metastasis effects in vitro and in vivo.
In addition, PEG-tAHP-DRI has no obvious toxicity and harmful effects on the heart, liver and kidney, and is naturally inert to DR6-related signal transduction pathways, which provides enlightenment for the safe clinical application of PEG-tAHP-DRI.
In summary, this study provides a promising polymer coupling agent targeting DR6 for future anti-blood metastasis therapies.
Reference message: https://onlinelibrary.
wiley.
com/doi/10.
1002/advs.
202003558
