Peptide-drug Conjugate Information
General Information of This Peptide-drug Conjugate (PDC)
| PDC ID |
PDC_00250
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| PDC Name |
MTX-cLABL
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| PDC Status |
Investigative
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| Indication |
In total 1 Indication(s)
Inflammation
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| Structure |
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| Peptide Name |
cLABL
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Peptide Info | ||||
| Receptor Name |
Intercellular adhesion molecule 1 (ICAM1)
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Receptor Info | ||||
| Drug Name |
Methotrexate
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Drug Info | ||||
| Therapeutic Target |
Reduced folate transporter (SLC19A1)
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Target Info | ||||
| Linker Name |
Glu -carboxylic acid
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Linker Info | ||||
| Peptide Modified Type |
Cyclization modification
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| Modified Segment |
Side-chain cyclization
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| Formula |
C65H92N20O26S2
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| #Ro5 Violations (Lipinski): 5 | Molecular Weight | 1633.699 | ||||
| Lipid-water partition coefficient (xlogp) | -7.8435 | |||||
| Hydrogen Bond Donor Count (hbonddonor) | 23 | |||||
| Hydrogen Bond Acceptor Count (hbondacc) | 30 | |||||
| Rotatable Bond Count (rotbonds) | 26 | |||||
Full List of Activity Data of This Peptide-drug Conjugate
Revealed Based on the Cell Line Data
| Experiment 1 Reporting the Activity Data of This PDC | [1] | ||||
| Indication | Inflammation | ||||
| Efficacy Data | Half Maximal Inhibitory Concentration (IC50) | > 100 µM | |||
| Administration Time | 1 h | ||||
| Evaluation Method | Propidium iodide (PI) assay | ||||
| MOA of PDC |
In this study, cLABL and cLBEL peptides were linked to methotrexate (MTX) to produce MTX-cLABL and MTX-cLBEL conjugates. The goal was to target MTX to human coronary artery endothelial cells (HCAEC) via the ICAM-1 receptor to lower MTX toxicity and side effects. The biological abilities of MTX-cLABL, MTX-cLBEL, cLABL, cLBEL, and MTX were compared by their activities to inhibit binding of anti-ICAM-1 mAb to ICAM-1 on the surface of HCAEC. In addition, these molecules were compared in inhibiting T cell adhesion to HCAEC monolayers. Finally, their activities in suppressing IL-6 and IL-8 production as inflammatory cytokines were determined. The toxicities of MTX-cLABL and MTX-cLBEL conjugates were also determined relative to MTX alone as well as cLABL and cLBEL peptides.
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| Description |
We next determined whether treatment of HCAEC and Molt-3 T cells with peptides, MTX, and MTX-peptide conjugates resulted in inhibition of cell proliferation. Both HCAEC and Molt-3 T cells were affected by test compound in different levels. None of the molecules caused growth stimulation or total culture extinction. A net cell killing of HCAEC was observed upon treatment with MTX at all test concentrations while MTX affected net killing at ≥1.0 uM in Molt-3 T cells. The MTX-peptide conjugates were less toxic than MTX. In HCAEC, the net cell killing was at lower concentration for MTX at ≥0.1 uM compared to MTX-peptide conjugates at ≥500 uM. The net cell killing of Molt-3 T cells was found at ≥1.0 uM for MTX and ≥50 uM for MTX-peptide conjugates. For all test concentrations, the conjugates only resulted in HCAEC partial growth inhibition. For Molt-3 T cells, a total growth inhibition emerged at 100 uM for cLABL and cLBEL; however, 500 uM cLABL and cLBEL did not cause total cell killing for T cells.
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| In Vitro Model | human coronary artery endothelial cell | Human coronary artery endothelial cell | Homo sapiens | ||
| Experiment 2 Reporting the Activity Data of This PDC | [1] | ||||
| Indication | Inflammation | ||||
| Efficacy Data | Half Maximal Inhibitory Concentration (IC50) | > 500 µM | |||
| Administration Time | 1 h | ||||
| Evaluation Method | Propidium iodide (PI) assay | ||||
| MOA of PDC |
In this study, cLABL and cLBEL peptides were linked to methotrexate (MTX) to produce MTX-cLABL and MTX-cLBEL conjugates. The goal was to target MTX to human coronary artery endothelial cells (HCAEC) via the ICAM-1 receptor to lower MTX toxicity and side effects. The biological abilities of MTX-cLABL, MTX-cLBEL, cLABL, cLBEL, and MTX were compared by their activities to inhibit binding of anti-ICAM-1 mAb to ICAM-1 on the surface of HCAEC. In addition, these molecules were compared in inhibiting T cell adhesion to HCAEC monolayers. Finally, their activities in suppressing IL-6 and IL-8 production as inflammatory cytokines were determined. The toxicities of MTX-cLABL and MTX-cLBEL conjugates were also determined relative to MTX alone as well as cLABL and cLBEL peptides.
Click to Show/Hide
|
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| Description |
We next determined whether treatment of HCAEC and Molt-3 T cells with peptides, MTX, and MTX-peptide conjugates resulted in inhibition of cell proliferation. Both HCAEC and Molt-3 T cells were affected by test compound in different levels. None of the molecules caused growth stimulation or total culture extinction. A net cell killing of HCAEC was observed upon treatment with MTX at all test concentrations while MTX affected net killing at ≥1.0 uM in Molt-3 T cells. The MTX-peptide conjugates were less toxic than MTX. In HCAEC, the net cell killing was at lower concentration for MTX at ≥0.1 uM compared to MTX-peptide conjugates at ≥500 uM. The net cell killing of Molt-3 T cells was found at ≥1.0 uM for MTX and ≥50 uM for MTX-peptide conjugates. For all test concentrations, the conjugates only resulted in HCAEC partial growth inhibition. For Molt-3 T cells, a total growth inhibition emerged at 100 uM for cLABL and cLBEL; however, 500 uM cLABL and cLBEL did not cause total cell killing for T cells.
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| In Vitro Model | Adult T acute lymphoblastic leukemia | Molt-3 T cell | CVCL_0624 | ||
References