Peptide-drug Conjugate Information
General Information of This Peptide-drug Conjugate (PDC)
| PDC ID |
PDC_02022
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| PDC Name |
Ac-ECM
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| PDC Status |
Investigative
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| Indication |
In total 1 Indication(s)
SARS-CoV infection
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| Structure |
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| Peptide Name |
CM8
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Peptide Info | ||||
| Drug Name |
5-Amino-2-Methyl-N-[(1r)-1-Naphthalen-1-Ylethyl]benzamide
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Drug Info | ||||
| Linker Name |
Amide bond
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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 |
C57H78N13O9S2+
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| #Ro5 Violations (Lipinski): 4 | Molecular Weight | 1153.467 | ||||
| Lipid-water partition coefficient (xlogp) | 1.88079 | |||||
| Hydrogen Bond Donor Count (hbonddonor) | 13 | |||||
| Hydrogen Bond Acceptor Count (hbondacc) | 12 | |||||
| Rotatable Bond Count (rotbonds) | 19 | |||||
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 | SARS-CoV infection | ||||
| Efficacy Data | Half maximal inhibitory concentration (IC50) |
8.63 ± 0.55 μM
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| MOA of PDC |
Peptide-drug conjugates (PDCs) are a class of novel molecules widely designed and synthesized for delivering drug payloads. In this work, we designed a novel PDC in which the GRL0617 was linked to the sulfonium-tethered peptides derived from PLpro-specific substrate LRGG. This conjugate could covalently label PLpro active site C111. Two conjugates EM-C and EC-M showed a promising in vitro IC50 of 7.40 ± 0.37 and 8.63 ± 0.55 μM, respectively. Both conjugates could effectively inhibit anti-ISGylation activities of PLpro in cells, and there is low toxicity of PDC EC-M and EM-C in different cells.
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| Description |
The enzymatic activities of SARS-CoV-2 PLpro were tested using the fluorogenic peptide substrate LRGG-AMC. The sulfonium-tethered peptides without GRL0617 could not efficiently inhibit SARS-CoV-2 PLpro, while the sulfonium-tethered peptide conjugate GRL0617 has a better inhibition ability. Specifically, IC50 values of EM-C and EC-M were 7.40 ± 0.37 and 8.63 ± 0.55 μM, respectively. Enzymatic activities of PLpro were inhibited by different PDCs or GRL0617. (A) Enzymatic activity of SARS-CoV-2 PLpro was inhibited by different PDCs or GRL0617. The activity assay was performed using the peptide LRGG-ACC as a substrate. Error bars represent standard errors of mean of at least three independent measurements. (B) IC50 of different PDCs or GRL0617 in SARS-CoV-2 PLpro. IC50 of EM-C was 7.40 ± 0.37 μM. IC50 of EC-M was 8.63 ± 0.55 μM. IC50 of ELRGG was 15.38 ± 1.63 μM. IC50 of GRL0617 was 2.64 ± 0.34 μM. (C) Enzymatic activity of SARS-CoV PLpro was inhibited by different PDCs or GRL0617. (D) Enzyme activity of MERS PLpro was inhibited by different PDCs or GRL0617. Also, we tested the peptide inhibition ability to SARS-CoV PLpro and MERS PLpro. There is a high sequence identity (83%) between the SARS-CoV-2 PLpro and SARS-CoV PLpro. The IC50 value of EM-C against SARS-CoV PLpro was 3.43 ± 0.54 μM, close to GRL0617 (IC50 = 2.60 ± 0.05 μM). Its linear analogue showed weaker inhibition. The GRL0617, EC-M, EM-C, and ELRGG could not inhibit MERS PLpro. Both EM-C and EC-M showed better inhibition for SARS-CoV PLpro than SARS-CoV-2 PLpro.
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| In Vitro Model | COVID-19 | SARS-CoV-2 | 2697049 | ||
| Experiment 2 Reporting the Activity Data of This PDC | [1] | ||||
| Indication | SARS-CoV infection | ||||
| Efficacy Data | Half maximal inhibitory concentration (IC50) |
16.38±0.81 μM
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| MOA of PDC |
Peptide-drug conjugates (PDCs) are a class of novel molecules widely designed and synthesized for delivering drug payloads. In this work, we designed a novel PDC in which the GRL0617 was linked to the sulfonium-tethered peptides derived from PLpro-specific substrate LRGG. This conjugate could covalently label PLpro active site C111. Two conjugates EM-C and EC-M showed a promising in vitro IC50 of 7.40 ± 0.37 and 8.63 ± 0.55 μM, respectively. Both conjugates could effectively inhibit anti-ISGylation activities of PLpro in cells, and there is low toxicity of PDC EC-M and EM-C in different cells.
Click to Show/Hide
|
||||
| Description |
The enzymatic activities of SARS-CoV-2 PLpro were tested using the fluorogenic peptide substrate LRGG-AMC. The sulfonium-tethered peptides without GRL0617 could not efficiently inhibit SARS-CoV-2 PLpro, while the sulfonium-tethered peptide conjugate GRL0617 has a better inhibition ability. Specifically, IC50 values of EM-C and EC-M were 7.40 ± 0.37 and 8.63 ± 0.55 μM, respectively. Enzymatic activities of PLpro were inhibited by different PDCs or GRL0617. (A) Enzymatic activity of SARS-CoV-2 PLpro was inhibited by different PDCs or GRL0617. The activity assay was performed using the peptide LRGG-ACC as a substrate. Error bars represent standard errors of mean of at least three independent measurements. (B) IC50 of different PDCs or GRL0617 in SARS-CoV-2 PLpro. IC50 of EM-C was 7.40 ± 0.37 μM. IC50 of EC-M was 8.63 ± 0.55 μM. IC50 of ELRGG was 15.38 ± 1.63 μM. IC50 of GRL0617 was 2.64 ± 0.34 μM. (C) Enzymatic activity of SARS-CoV PLpro was inhibited by different PDCs or GRL0617. (D) Enzyme activity of MERS PLpro was inhibited by different PDCs or GRL0617. Also, we tested the peptide inhibition ability to SARS-CoV PLpro and MERS PLpro. There is a high sequence identity (83%) between the SARS-CoV-2 PLpro and SARS-CoV PLpro. The IC50 value of EM-C against SARS-CoV PLpro was 3.43 ± 0.54 μM, close to GRL0617 (IC50 = 2.60 ± 0.05 μM). Its linear analogue showed weaker inhibition. The GRL0617, EC-M, EM-C, and ELRGG could not inhibit MERS PLpro. Both EM-C and EC-M showed better inhibition for SARS-CoV PLpro than SARS-CoV-2 PLpro.
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| In Vitro Model | COVID-19 | SARS-CoV-2 | 2697049 | ||
References