aCx26-pep

Our first new peptide for 2024, aCx26-pep, is a peptide consisting of the gap junction protein connexin 26 (Cx26) cytosolic tail sequence, coupled to the cell permeant peptide antennapedia, first disclosed by Mulkearns-Hubert and colleagues in Molecular Cancer Therapeutics

Triple-negative breast cancer (TNBC) is a frequently lethal breast cancer subtype with limited treatment options. The authors identified a protein complex unique to TNBC composed of the gap junction protein connexin 26 (Cx26), the pluripotency transcription factor NANOG, and focal adhesion kinase (FAK) and sought to determine whether a peptide mimetic of the interaction region of Cx26 attenuated tumour growth.  Peptides were based on Cx26 juxtamembrane domains and binding studies revealed that the Cx26 C-terminal tail and intracellular loop bound to NANOG and FAK with submicromolar-to-micromolar affinity and that a 5-amino acid sequence in the C-terminal tail of Cx26 (RYCSG) was sufficient for binding. Peptides with high affinity were engineered with a cell-penetrating antennapedia sequence and assessed in functional assays including cell proliferation, tumoursphere formation and in vivo tumour growth. The cell-penetrating Cx26 peptide (aCx26-pep) disrupted self-renewal while reducing nuclear FAK and NANOG and inhibiting NANOG target gene expression in TNBC cells, but not luminal mammary epithelial cells. In vivo, aCx26-pep reduced tumour growth and proliferation and induced cell death.    

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