Disrupting Cancer Signaling with Precision: The Promise of GO-Pep as a Targeted BAG-1 Inhibitor
For our May Journal Club, we review a recently published article in Communications Biology. Özge Tatli1 and colleagues report the development of GO-Pep, a rationally designed peptide that disrupts the interaction between the co-chaperone BAG-1 and the kinase c-Raf—two proteins implicated in promoting cancer cell survival through the MAPK/ERK signaling pathway. Using hydrogen-deuterium exchange mass spectrometry (HDX-MS), the team mapped the critical binding interface between BAG-1 and a 20-amino acid stretch of c-Raf, which they used to construct GO-Pep. This peptide, fused to a cell-penetrating motif, successfully entered cancer cells and displaced c-Raf from its complex with BAG-1, leading to a reduction in downstream MAPK signaling. GO-Pep treatment resulted in increased apoptosis and reduced proliferation in BAG-1-overexpressing cancer cell lines, with minimal cytotoxicity observed in non-cancerous cells—highlighting its therapeutic potential.
This work exemplifies how detailed protein interaction mapping can drive the design of peptides that selectively modulate protein-protein interactions (PPIs), long considered challenging drug targets. GO-Pep’s success in vitro sets the stage for further optimization, including stability enhancement and targeted delivery strategies, to realize its translational potential in cancer therapy. For the peptide community at BPF, GO-Pep is a compelling case of structure-guided PPI disruption that aligns with broader efforts to expand the druggable proteome using peptide-based modalities.
1Link to open access article: https://doi.org/10.1038/s42003-024-07419-4
Tatlı, Ö., Eyüpoğlu, E., Er, Y., Aytekin, E., Yılmaz, B., Cingöz, A., Akgül, C., & Doğanlar, O. (2025). A BAG-1-inhibitory peptide, GO-Pep, suppresses c-Raf activity in cancer. Communications Biology, 8, Article 235.
Kevin McCowen
Treasurer Boulder Peptide Foundation, Member Board of Directors
President MAC-Lab
linkedin.com/in/kevin-mccowen-a40b8030
Read previous editions of the BPF Journal Club series: https://www.boulderpeptide.org/journal-club