ArticleCommunications biology2025
A BAG-1-inhibitory peptide, GO-Pep, suppresses c-Raf activity in cancer.
Article in Communications biology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
BAG-1 interacts with multiple partners, particularly with c-Raf, and promotes cancer cell survival. Hence, modulating the BAG-1-associated interactions with novel inhibitors could provide benefit for cancer therapy. Using HDX-MS, we first demonstrate the higher-order structure of BAG-1S and identify a potential "druggable" site on its BAG domain. An LC-MS/MS-coupled cell-free binding experiment is then used to map the BAG-1S:c-Raf interface, uncovering a 20-amino acid-length region of BAG-1S that is most likely to interact with c-Raf. Site-directed mutagenesis experiments reveal that K149 and L156 are hot spots for BAG-1S:c-Raf interaction, and their substitutions with alanine attenuate the survival of MCF-7 cells. We then show that a peptide derived from the BAG-1S-interacting c-Raf region hinders BAG domain-associated partners. The peptide, engineered with a cell-penetrating peptide motif, can penetrate cells, and it induces apoptosis in cancer cells. The anticancer activity of the peptide might lead to improved treatments for BAG-1-overexpressed and/or MAPK-driven tumors.
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