Peptide-drug Conjugate Information
General Information of This Peptide-drug Conjugate (PDC)
| PDC ID |
PDC_01128
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| PDC Name |
Tripeptide 46 - Beta-carboline derivative conjugate 1
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| PDC Status |
Investigative
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| Indication |
In total 1 Indication(s)
Mesenteric ischemia and reperfusion injury
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| Structure |
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| Peptide Name |
GFW
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Peptide Info | ||||
| Drug Name |
Beta-carboline derivative
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Drug Info | ||||
| Linker Name |
Amide bond
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Linker Info | ||||
| Formula |
C34H34N6O5
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| #Ro5 Violations (Lipinski): 3 | Molecular Weight | 606.683 | ||||
| Lipid-water partition coefficient (xlogp) | 2.3193 | |||||
| Hydrogen Bond Donor Count (hbonddonor) | 7 | |||||
| Hydrogen Bond Acceptor Count (hbondacc) | 5 | |||||
| Rotatable Bond Count (rotbonds) | 11 | |||||
Full List of Activity Data of This Peptide-drug Conjugate
Obtained from the Model Organism Data
| Experiment 1 Reporting the Activity Data of This PDC | [1] | ||||
| Indication | Mesenteric ischemia and reperfusion injury | ||||
| Efficacy Data | Edema inhibition rate |
37.50%
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| Administration Time | 30 min | ||||
| Administration Dosage | 0.15mmol/kg | ||||
| MOA of PDC |
It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of β-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that β-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel β-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury.
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| Description |
All compounds were evaluated for anti-inflammatory capacity in a xylene-induced ear edema model. Briefly, this in vivo assay involves oral administration of test compounds in 0.5% carboxymethyl cellulose (CMC) suspension. Each compound was initially tested at 0.15 mmol/kg, and all revealed significant protection against xylene-induced inflammation, suggesting potent anti-inflammatory capacity. Since compounds (4a,e,k,o,p) exhibit good analgesic activities in the tail flick assay and superior anti-inflammatory activities in the xylene-induced ear edema model, these compounds were then examined in the same assay at lower doses to establish the detailed pharmacological activity profile. From Table 4, we noticed a dose-dependent anti-inflammatory response for 4a,e,k,o,p.
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| In Vivo Model | Male ICR mice xylene-induced ear edema model. | ||||
| Experiment 2 Reporting the Activity Data of This PDC | [1] | ||||
| Indication | Mesenteric ischemia and reperfusion injury | ||||
| Efficacy Data | Edema weight |
2.05 ± 0.76 mg
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| Administration Time | 30 min | ||||
| Administration Dosage | 0.15mmol/kg | ||||
| MOA of PDC |
It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of β-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that β-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel β-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury.
Click to Show/Hide
|
||||
| Description |
All compounds were evaluated for anti-inflammatory capacity in a xylene-induced ear edema model. Briefly, this in vivo assay involves oral administration of test compounds in 0.5% carboxymethyl cellulose (CMC) suspension. Each compound was initially tested at 0.15 mmol/kg, and all revealed significant protection against xylene-induced inflammation, suggesting potent anti-inflammatory capacity. Since compounds (4a,e,k,o,p) exhibit good analgesic activities in the tail flick assay and superior anti-inflammatory activities in the xylene-induced ear edema model, these compounds were then examined in the same assay at lower doses to establish the detailed pharmacological activity profile. From Table 4, we noticed a dose-dependent anti-inflammatory response for 4a,e,k,o,p.
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| In Vivo Model | Male ICR mice xylene-induced ear edema model. | ||||
| Experiment 3 Reporting the Activity Data of This PDC | [1] | ||||
| Indication | Mesenteric ischemia and reperfusion injury | ||||
| Efficacy Data | Pain threshold variation |
10.36 ± 22.24%
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| Administration Time | 30min | ||||
| Administration Dosage | 0.15mmol/kg | ||||
| Evaluation Method | Tail flick method | ||||
| MOA of PDC |
It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of β-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that β-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel β-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury.
Click to Show/Hide
|
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| Description |
All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines.
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| In Vivo Model | Male ICR mice. | ||||
| Experiment 4 Reporting the Activity Data of This PDC | [1] | ||||
| Indication | Mesenteric ischemia and reperfusion injury | ||||
| Efficacy Data | Pain threshold variation |
14.36 ± 28.12%
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| Administration Time | 180min | ||||
| Administration Dosage | 0.15mmol/kg | ||||
| Evaluation Method | Tail flick method | ||||
| MOA of PDC |
It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of β-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that β-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel β-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury.
Click to Show/Hide
|
||||
| Description |
All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines.
Click to Show/Hide
|
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| In Vivo Model | Male ICR mice. | ||||
| Experiment 5 Reporting the Activity Data of This PDC | [1] | ||||
| Indication | Mesenteric ischemia and reperfusion injury | ||||
| Efficacy Data | Pain threshold variation |
22.37 ± 34.30%
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| Administration Time | 150min | ||||
| Administration Dosage | 0.15mmol/kg | ||||
| Evaluation Method | Tail flick method | ||||
| MOA of PDC |
It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of β-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that β-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel β-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury.
Click to Show/Hide
|
||||
| Description |
All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines.
Click to Show/Hide
|
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| In Vivo Model | Male ICR mice. | ||||
| Experiment 6 Reporting the Activity Data of This PDC | [1] | ||||
| Indication | Mesenteric ischemia and reperfusion injury | ||||
| Efficacy Data | Pain threshold variation |
40.78 ± 32.03%
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| Administration Time | 60min | ||||
| Administration Dosage | 0.15mmol/kg | ||||
| Evaluation Method | Tail flick method | ||||
| MOA of PDC |
It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of β-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that β-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel β-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury.
Click to Show/Hide
|
||||
| Description |
All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines.
Click to Show/Hide
|
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| In Vivo Model | Male ICR mice. | ||||
| Experiment 7 Reporting the Activity Data of This PDC | [1] | ||||
| Indication | Mesenteric ischemia and reperfusion injury | ||||
| Efficacy Data | Pain threshold variation |
46.45 ± 5.46%
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| Administration Time | 90min | ||||
| Administration Dosage | 0.15mmol/kg | ||||
| Evaluation Method | Tail flick method | ||||
| MOA of PDC |
It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of β-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that β-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel β-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury.
Click to Show/Hide
|
||||
| Description |
All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines.
Click to Show/Hide
|
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| In Vivo Model | Male ICR mice. | ||||
| Experiment 8 Reporting the Activity Data of This PDC | [1] | ||||
| Indication | Mesenteric ischemia and reperfusion injury | ||||
| Efficacy Data | Pain threshold variation |
49.09 ± 29.03%
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| Administration Time | 120min | ||||
| Administration Dosage | 0.15mmol/kg | ||||
| Evaluation Method | Tail flick method | ||||
| MOA of PDC |
It has been reported that some short peptides with certain sequences may be used as analgesic agents. In addition, our recent research findings indicated that some tripeptides with AA-Phe-Trp sequence present good analgesic activities. Since reactive oxygen species (ROS) and inflammatory leukocytes play an important role in the pathogenesis of I/R injury, antioxidant therapy and inhibition of post-ischemic neutrophil infiltration may have therapeutic efficacy during I/R injury. Ideally, I/R injury can be treated by a combination of the therapeutic agents. Generally, when two synergistic agents are administered individually but simultaneously, they will be transported to the site of action with different efficiencies. However, there are potential advantages in giving the co-administered agents as a single chemical entity. It is desirable to have the two synergistic agents reach a site simultaneously. Considering the antioxidant properties of β-carboline alkaloids coupled with the analgesic activity observed with AA-Phe-Trp tripeptides, we hypothesized that β-carboline and tripeptide (AA-Phe-Trp) conjugates might exhibit both enhanced antioxidant and analgesic activities. To test this hypothesis, we have synthesized a series of novel β-carboline-tripeptide (AA-Phe-Trp) conjugates, and evaluated their biological capacity to protect against mesenteric I/R injury.
Click to Show/Hide
|
||||
| Description |
All compounds were prescreened for analgesic activity at a dose of 0.15 mmol/kg. For each animal, pain thresholds were estimated at 30, 60, 120, 150 and 180 min following vehicle or drug administration. -Carboline-tripeptide conjugates exhibited moderate to good analgesic activity, with compounds 4a,e,k,l,o,p demonstrating especially good analgesic properties. All pain thresholds were increased after 30 min, yet maximal pain thresholds occurred at different time points for various synthetic derivatives. For example, the maximal pain thresholds for 4a,c,e,h,m were observed after 60 min, whereas for 4d,g,k,l,n,o,p this value was 90 min, and for 4b,f,i,q,r, 120 min post drug administration. The duration of the analgesic action of 4a,b,c,d,e,f,i,j was 150 min, while the same value for 4k,l,m,n,o,p was 180 min. We speculate that the physiological difference in analgesic activity is closely related to the tripeptide sequences of the -carbolines.
Click to Show/Hide
|
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| In Vivo Model | Male ICR mice. | ||||
References