Comparison between clickable cyclic TAT and penetratin for delivery of cyclic and bicyclic-peptide cargos

Ketav Kulkarni, Jianrong Sang, Xiuquan Ma, Jacqueline A. Wilce

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Growth-receptor bound 7 (Grb7) is an adapter protein identified as a target for the inhibition of signaling pathways in breast and other cancers. We have previously developed cyclic and bicyclic G7-peptide inhibitors, targeted to the Grb7-SH2 domain, and used the cell-penetrating peptide (CPP) penetratin to deliver them to cells to test their biological effects. Here we used an alternative peptide known as cyclic TAT (cTAT) to determine whether it would be more effective for the delivery of the G7-peptides. We report the synthesis of propargyl-cTAT for the conjugation to azido-peptides G7-18NATE and G7-B7M2 via click chemistry. We then compare these peptides with G7-18NATE-Pen and G7-B7M2-Pen for their ability to inhibit signaling, proliferation, migration and, invasion of SKBR-3 and MDA-MB-231 breast cancer cell lines. We found both penetratin and cTAT conjugated G7-peptides were able to enter cells and exert biological effects but that cTAT was not more effective than penetratin for delivery of G7-18NATE, and neither CPP was highly effective for the delivery of G7-B7M2 in cell assays.

Original languageEnglish
Article numbere24163
Number of pages11
JournalPeptide Science
Issue number4
Publication statusPublished - Jul 2020


  • bicyclic peptide
  • cell invasion
  • cell migration
  • cell proliferation
  • cell-penetrating peptide
  • click chemistry
  • cTAT
  • Grb7
  • penetratin
  • SH2 domain
  • signaling

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