Repressor Activator Protein 1 (RAP1) and Telomeric Repeat Binding Factor 2 (TRF2) are physically interacting partners within the shelterin complex, which has telomere-related functions. Previous investigations suggest that RAP1 also binds to I?B kinases (IKK) in cytoplasm, where RAP1 recruits IKK to p65 of NF- ?B and subsequently activates NF-?B signaling pathway via phosphorylation of p65 S536.TRF2 and IKK share the same binding domain on RAP1. Potentially, a TRF2 peptide mimetic that binds to RAP1 with high affinity could block the protein�protein interactions of TRF2-RAP1 and IKK-RAP1.In this study, we optimizated the binding affinity, helical propensity, charge distribution and water solubility of a TRF2 peptide. This resulted in a 16-residude, cell-permeable, triazole-stapled peptide molecule which potently (Ki = 10 nM) binds to RAP1, down-regulates phosphorylated p65 of NF-?B and inhibits proliferation of MDA-MB-157 breast cancer cell.

Design of triazole-stapled TRF2 peptide inhibitors targeting NF-kB signaling pathway through direct binding to RAP1

248th National Meeting (2014)

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