Peptide-drug Conjugate Information | PDCdb

General Information of This Peptide-drug Conjugate (PDC)

PDC ID	PDC_00135
PDC Name	Dox-GLRKRLRKFRNK
PDC Status	Investigative
Indication	In total 1 Indication(s) Cervical carcinoma
Structure
2D MOL
Peptide Name	GLRKRLRKFRNK					Peptide Info
Receptor Name	Cell membrane
Drug Name	Doxorubicin					Drug Info
Therapeutic Target	DNA topoisomerase 2-alpha (TOP2A)					Target Info
Linker Name	S-(1-(2-carboxyethyl)-2,5-dioxopyrrolidin-3-yl)cysteine					Linker Info
Formula	C106H169N31O29S
#Ro5 Violations (Lipinski): 5	Molecular Weight			2373.773
	Lipid-water partition coefficient (xlogp)			-10.2859
	Hydrogen Bond Donor Count (hbonddonor)			32
	Hydrogen Bond Acceptor Count (hbondacc)			37
	Rotatable Bond Count (rotbonds)			76

Full List of Activity Data of This Peptide-drug Conjugate

Revealed Based on the Cell Line Data

Click To Hide/Show 1 Activity Data Related to This Level

Experiment 1 Reporting the Activity Data of This PDC					[1]
Indication	Cervical carcinoma
Efficacy Data	Half Maximal Effective Concentration (EC50)	27.01 µM
Administration Time	24 h
MOA of PDC	Herein, the design and synthesis of peptide-drug conjugates (PDCs) including different variants of the cell-penetrating peptide sC18 is presented. We first generated a series of novel sequence mutants of sC18 having either amino acid deletions and/or substitutions, and then tested their biological activity. The effects of histidine substituents were found to be not meaningful for sC18 uptake and cell selectivity. Moreover, building a nearly perfect amphipathic structure within a shortened sC18 derivative provided a peptide that was highly membrane-active, but also too cytotoxic. As a result, the most promising analog was sC18E, which stands out due to its higher uptake efficacy compared to parent sC18. In the last set of experiments, we let the peptides react with the cytotoxic drug doxorubicin by Thiol-Michael addition to form novel PDCs. Our results indicate that sC18E could be a more efficient drug carrier than parent sC18 for biomedical applications. However, cellular uptake using endocytosis and resulting entrapment of cargo inside vesicles is still a major critical step to overcome in CPP-containing peptide-drug development. Click to Show/Hide
Description	First, we probed the novel PDCs in non-cancerous human foreskin fibroblasts (HFF-1 cells). After 24 h treatment with different concentrations of PDCs, HFF-1 cells were still viable, while after adding doxorubicin viability was decreased up to 72%. In comparison, when we elucidated PDC activity in HeLa cells and exposed them for 24 h to various concentrations of the conjugates (2.5-70 μM), all of the PDCs, as well as free Dox, exhibited EC50 values in the lower micromolar range (PDC-1: 15.34 μM, PDC-2: 14.47 μM, PDC-3: 27.01 μM, Dox: 6.78 μM data not shown). The higher activity compared to HFF cells might be attributed to the fact that the PDCs were internalized to far less of an extent into the non-cancerous cell line. This observation might be advantageous and could reflect some selectivity of the more basic and positively charged peptides towards cancerous cells. We also noted that the obtained EC50 values somehow agreed with the results of the former assays. For example, sC18E was taken up to a significantly higher extent compared to sC18* and should, therefore, exhibit higher activity, e.g., drug delivery. However, surprisingly, the EC50 values of the PDCs containing sC18 and sC18E were quite similar, although sC18E significantly outcompeted sC18 in internalization activity. Click to Show/Hide
In Vitro Model	Endocervical adenocarcinoma	HeLa cell		CVCL_0030

References

Ref 1	Comparing Variants of the Cell-Penetrating Peptide sC18 to Design Peptide-Drug Conjugates. Molecules. 2022 Oct 7;27(19):6656. doi: 10.3390/molecules27196656.